CN107213463A - Developmental effect of the Interleukin 25 in psoriasis - Google Patents
Developmental effect of the Interleukin 25 in psoriasis Download PDFInfo
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- CN107213463A CN107213463A CN201710375612.2A CN201710375612A CN107213463A CN 107213463 A CN107213463 A CN 107213463A CN 201710375612 A CN201710375612 A CN 201710375612A CN 107213463 A CN107213463 A CN 107213463A
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- interleukin
- functional analogue
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- stat3
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/19—Cytokines; Lymphokines; Interferons
- A61K38/20—Interleukins [IL]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/0005—Vertebrate antigens
- A61K39/0008—Antigens related to auto-immune diseases; Preparations to induce self-tolerance
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
- G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
- G01N33/5044—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics involving specific cell types
- G01N33/5047—Cells of the immune system
Abstract
The present invention proposes purposes, the method for immune cell activated, the method that suppresses immune cell activation, vaccine and the method for screening medicine of the reagent in the purposes in preparing medicine, preparation in medicine is prepared.The medicine is used to suppress immune system activation, and the reagent is selected from least one of following：(1) Interleukin 25 antagonist or its functional analogue；(2) IL 17RB antagonists or its functional analogue；(3) STAT3 antagonists or its functional analogue；(4) interleukin-17 antagonist or its functional analogue；And (5) Interleukin 25, IL 17RB, interleukin-17 or STAT3 expression inhibiting agent.The reagent of the present invention can effectively suppress activated immune cell, so as to suppress the activation of immune system.
Description
Technical field
The present invention relates to biological field.In particular it relates to developmental effect of the Interleukin 25 in psoriasis.More
In particular it relates to which reagent is in the purposes in preparing medicine, preparation purposes in medicine is prepared, immune cell activated
Method, the method for suppressing immune cell activation, vaccine and the method for screening medicine.
Background technology
Psoriasis is commonly called as psoriasis, is a kind of chronic inflammatory skin, and the course of disease is longer, there is easy tendency of recurrence, some diseases
Example almost cannot be cured all one's life.The disease is fallen ill based on person between twenty and fifty, and the healthy and mental status influence on patient is larger.Its feature
It is the hyper-proliferative of epidermis and the inflammatory cell infiltration of corium, clinical manifestation is based on erythema, the scales of skin that peel off, and whole body can fall ill, with
It is relatively conventional that scalp, four limbs stretch side, aggravates in the winter time more.
However, still being required study for psoriasis at present.
The content of the invention
It is contemplated that at least solving at least one technical problem present in prior art to a certain extent.Therefore,
The present invention propose reagent purposes in medicine is prepared of the purposes in preparing medicine, preparation, the method for immune cell activated,
Suppress method, vaccine and the method for screening medicine of immune cell activation.
In one aspect of the invention, the present invention proposes purposes of the reagent in medicine is prepared.According to the reality of the present invention
Example is applied, the medicine is used to suppress immune system activation, and the reagent is selected from least one of following：(1) Interleukin 25 antagonism
Agent or its functional analogue；(2) IL-17RB antagonists or its functional analogue；(3) STAT3 antagonists or its functional analogue；
(4) interleukin-17 antagonist or its functional analogue；And (5) Interleukin 25, IL-17RB, interleukin-17 or STAT3 table
Up to inhibitor.Thus, reagent according to embodiments of the present invention can effectively suppress activated immune cell, so as to suppress siberian crabapple
The activation of system.
Embodiments in accordance with the present invention, purposes of the mentioned reagent in medicine is prepared can also have following supplementary technology special
Levy：
Embodiments in accordance with the present invention, the medicine is used to treat autoimmune disease.Thus, according to present invention implementation
The reagent of example can effectively suppress activated immune cell, suppress the activation of immune system, so as to play treatment LADA
The effect of disease.
Embodiments in accordance with the present invention, the medicine is used to treat psoriasis.Thus, reagent according to embodiments of the present invention
Activated immune cell can effectively be suppressed, suppress the activation of immune system, so as to play the effect for the treatment of psoriasis.
In another aspect of this invention, the present invention proposes purposes of the preparation in medicine is prepared.According to the reality of the present invention
Example is applied, the medicine is used for activating immune system, and the preparation is selected from least one of following：(a) Interleukin 25 or its function
Analog；(b) secretion Interleukin 25 or the cell of its functional analogue；(c) Interleukin 25 activator or its analog；(d)IL-
17RB or its functional analogue；(e) IL-17RB activators or its functional analogue；(f) STAT3 or its functional analogue；(g)
Interleukin-17 or its functional analogue；And the expression accelerator of any one of (h) (a)~(g).Thus, according to present invention implementation
The preparation of example can be effectively facilitated activated immune cell, so that activating immune system.
Embodiments in accordance with the present invention, the medicine is used to treat immunodefiiciency disease.Thus, according to present invention implementation
The preparation of example can be effectively facilitated activated immune cell, activating immune system, so as to play treatment immunodefiiciency disease
Effect.
Embodiments in accordance with the present invention, the cell of the secretion Interleukin 25 is keratinocyte.Thus, according to this hair
The preparation of bright embodiment can be effectively facilitated activated immune cell, activating immune system.
In still another aspect of the invention, the present invention proposes a kind of method of immune cell activated.According to the reality of the present invention
Example is applied, methods described includes：Immunocyte is set to be contacted with selected from least one of following：(a) Interleukin 25 or its function are similar
Thing；(b) secretion Interleukin 25 or the cell of its functional analogue；(c) Interleukin 25 activator or its analog；(d)IL-17RB
Or its functional analogue；(e) IL-17RB activators or its functional analogue；(f) STAT3 or its functional analogue；(g) it is white to be situated between
Element 17 or its functional analogue；And the expression accelerator of any one of (h) (a)~(g).Thus, it is according to embodiments of the present invention
Method being capable of effectively immune cell activated.
In still another aspect of the invention, the present invention proposes a kind of method for suppressing immune cell activation.According to the present invention
Embodiment, methods described includes：Immunocyte is set to be contacted with selected from least one of following：(1) Interleukin 25 antagonist or
Its functional analogue；(2) IL-17RB antagonists or its functional analogue；(3) STAT3 antagonists or its functional analogue；(4)
Interleukin-17 antagonist or its functional analogue；And (5) Interleukin 25, IL-17RB, interleukin-17 or STAT3 expression
Inhibitor.Thus, method according to embodiments of the present invention can effectively suppress immune cell activation.
In still another aspect of the invention, the present invention proposes a kind of vaccine.Embodiments in accordance with the present invention, the vaccine contains
There is antigen and selected from least one of following：(a) Interleukin 25 or its functional analogue；(b) secretion Interleukin 25 or its work(
The cell of energy analog；(c) Interleukin 25 activator or its analog；(d) IL-17RB or its functional analogue；(e)IL-
17RB activators or its functional analogue；(f) STAT3 or its functional analogue；(g) interleukin-17 or its functional analogue；With
And the expression accelerator of any one of (h) (a)~(g).Thus, method according to embodiments of the present invention can be effectively facilitated immune
Cell activation, so that activating immune system, produces corresponding antibody.
In still another aspect of the invention, the present invention proposes a kind of method for screening medicine.Embodiments in accordance with the present invention,
Methods described includes：By candidate agent and cells contacting, the cell secretes Interleukin 25；And before and after the determination contact,
The Interleukin 25 expression of the cell, wherein, the Interleukin 25 expression rise, is the candidate agent after the contact
It is used as the instruction of immunodefiiciency disease medicine；The Interleukin 25 expression reduction after the contact, is that the candidate agent is made
For the instruction of autoimmune disease medicine.Thus, resulted in using the method for screening medicine according to embodiments of the present invention
Autoimmune disease medicine or immune activation medicine.
The additional aspect and advantage of the present invention will be set forth in part in the description, and will partly become from the following description
Obtain substantially, or recognized by the practice of the present invention.
Brief description of the drawings
The above-mentioned and/or additional aspect and advantage of the present invention will become from description of the accompanying drawings below to embodiment is combined
Substantially and be readily appreciated that, wherein：
Fig. 1 shows that the analysis of Interleukin 25 inducing mouse pachyderma according to an embodiment of the invention and inflammation is shown
It is intended to；
Fig. 2 shows psoriatic skin inflammation according to an embodiment of the invention in the mouse that Interleukin 25 is knocked out
Phenotypic analysis schematic diagram；
Fig. 3, which is shown in the argyraemia growth course of interleukin-17 mediation according to an embodiment of the invention, originates white be situated between
The analysis schematic diagram of the expression of element 25；
Fig. 4 shows that the knockout of Interleukin 25 in keratinocyte according to an embodiment of the invention is considered to be worth doing to mouse silver
The analysis schematic diagram of disease symptoms influence；
Fig. 5 shows knockouts of the acceptor IL-17RB of Interleukin 25 according to an embodiment of the invention in non-medullary system
The analysis schematic diagram of the psoriatic phenotype influence induced IMQ；
Fig. 6 shows that psoriasis 25 according to an embodiment of the invention promotes the propagation of skin epidermal cells and regulation skin
Skin breeds the analysis schematic diagram with the expression of inflammation-related gene；
Fig. 7 shows adaptor protein ACT1 and STAT3 according to an embodiment of the invention signal path for white Jie
Element 25 induces the analysis schematic diagram of keratinocyte proliferation influence；And
Fig. 8 shows Interleukin 25 activation adaptor protein ACT1 and STAT3 according to an embodiment of the invention to play
The analysis schematic diagram of function on keratinocyte.
Embodiment
Embodiments of the invention are described below in detail.The embodiments described below is exemplary, is only used for explaining this hair
It is bright, and be not considered as limiting the invention.
Definition and general terms
The invention is intended to cover all replacement, modification and equivalent technical solutions, they are included in as claim is fixed
In the scope of the invention of justice.Those skilled in the art will appreciate that many and similar or equivalent method described herein and material
It can be used in the practice present invention.The present invention is not limited to method described herein and material.In the document combined, patent and class
One or more or contradict in the case of (include but is not limited to defined in term, terms different from the application like material
Using, described technology, etc.), it is defined by the application.
It will further be appreciated that some features of the present invention, are clearly visible, carried out in multiple independent embodiments
Description, but it is also possible to provide in combination in single embodiment.Conversely, the various features of the present invention, for brevity,
It is described in single embodiment, but it is also possible to individually or with arbitrarily suitable sub-portfolio provide.
Unless otherwise indicated, all scientific and technical terminologies used in the present invention have with those skilled in the art of the invention's
It is generally understood that identical implication.All patents of the present invention and public publication are integrally incorporated this hair by reference
It is bright.
There are obvious conflict, article " one " used herein, " one (kind) " unless otherwise indicated or in context
" described " is intended to include " at least one " or " one or more ".Therefore, these articles used herein refer to one or
The article of more than one (i.e. at least one) object.For example, " component " refers to one or more components, it is possible to have more than one
Component be taken into account in the embodiment of the embodiment and use or use.
Term " containing " is open language, i.e., including the content specified by the present invention, but be not precluded from otherwise
Content.
Term " functional analogue " refers to the material with identity function, its structure do not limit it is identical, as long as with identical
Or similar function.
Term " activator " refers to be combined with the acceptor of certain bioactive substance, and the material of the effect of the active material is presented
Or medicine.
Term " antagonist " refers to be combined with acceptor, but does not possess a class material of intrinsic activity.Antagonist is divided into competing
Striving property antagonist and noncompetitive antaganist.
" autoimmune disease " used in the present invention refer to body fluid or it is cell-mediated to body itself component should
Answer the set of any disease of the tissue damage of correlation.
It is immune thin in purposes in medicine is prepared of the purposes in preparing medicine, preparation, activation that the present invention proposes reagent
The method of born of the same parents, the method for suppressing immune cell activation, vaccine and the method for screening medicine.It will be carried out in detail respectively below
Description.
Purposes of the reagent in medicine is prepared
In one aspect of the invention, the present invention proposes purposes of the reagent in medicine is prepared.According to the reality of the present invention
Example is applied, the medicine is used to suppress immune system activation, and the reagent is selected from least one of following：(1) Interleukin 25 antagonism
Agent or its functional analogue；(2) IL-17RB antagonists or its functional analogue；(3) STAT3 antagonists or its functional analogue；
(4) interleukin-17 antagonist or its functional analogue；And (5) Interleukin 25, IL-17RB, interleukin-17 or STAT3 table
Up to inhibitor.
Inventor find, Interleukin 25 can activating immune system, cause the generation of some autoimmune diseases, for example
Psoriasis.Interleukin 25 high expression in the skin of psoriasis people and in psoriasis mouse model, is injected in mouse skin
Interleukin 25 can directly induce the phenotype of similar psoriasis, and the psoriasis that similar psoriatic phenotype is knocked out in Interleukin 25
It is decreased significantly in mouse model.Experiment in vitro proves that the stimulation of Interleukin 25 Human Keratinocytes can cause inflammation
The high expression of cell factor and chemotactic factor (CF), and this effect is realized by STAT3 activation.Inventor is by deeply grinding
Discovery is studied carefully, Interleukin 25 can stimulate its acceptor IL-17RB tyrosine phosphorylation, so as to recruit and activate STAT3 to produce
Raw downstream reaction.In addition, inventor has found, interleukin-17 can significantly induce the expression of Interleukin 25, and interleukin-17 is scarce
The expression for causing Interleukin 25 is lost no matter being all decreased significantly in mRNA level in-site or protein level.It is concluded, therefore, that interleukin
25 in the pathogenic process of psoriasis as interleukin-17 an important downstream elements.Therefore, Interleukin 25 antagonist or
Its functional analogue, IL-17RB antagonists or its functional analogue, STAT3 antagonists or its functional analogue, Interleukin 25 table
It can effectively suppress inflammatory cytokine up to inhibitor, the agent of IL-17RB expression inhibitings and the agent of STAT3 expression inhibitings and become
Change the high expression of the factor, suppress immune system activation, so as to play the effect of prevention or treatment autoimmune disease.
Embodiments in accordance with the present invention, the medicine is used to treat autoimmune disease.Thus, according to present invention implementation
The reagent of example can effectively suppress activated immune cell, suppress the activation of immune system, so as to play treatment LADA
The effect of disease.
Embodiments in accordance with the present invention, the medicine is used to treat psoriasis.Thus, reagent according to embodiments of the present invention
Activated immune cell can effectively be suppressed, suppress the activation of immune system, so as to play the effect for the treatment of psoriasis.
Purposes of the preparation in medicine is prepared
In another aspect of this invention, the present invention proposes purposes of the preparation in medicine is prepared.According to the reality of the present invention
Example is applied, the medicine is used for activating immune system, and the preparation is selected from least one of following：(a) Interleukin 25 or its function
Analog；(b) secretion Interleukin 25 or the cell of its functional analogue；(c) Interleukin 25 activator or its analog；(d)IL-
17RB or its functional analogue；(e) IL-17RB activators or its functional analogue；(f) STAT3 or its functional analogue；(g)
Interleukin-17 or its functional analogue；And the expression accelerator of any one of (h) (a)~(g).
Inventor find, Interleukin 25 can activating immune system, experiment in vitro prove Interleukin 25 cutin is formed carefully
The stimulation of born of the same parents can cause the high expression of cytokine profiles and chemotactic factor (CF), and this effect is real by STAT3 activation
Existing.Inventor has found that Interleukin 25 can stimulate its acceptor IL-17RB tyrosine phosphorylation by further investigation, so that
Recruit and activate STAT3 to produce downstream reaction.In addition, inventor has found, interleukin-17 can significantly induce Interleukin 25
Expression, and the missing of interleukin-17 cause Interleukin 25 expression no matter mRNA level in-site or protein level have it is notable under
Drop.It is concluded, therefore, that an important downstream elements of the Interleukin 25 as interleukin-17.Therefore, above-mentioned preparation can be effective
Ground promotes the high expression of immunocyte, activating immune system.
Embodiments in accordance with the present invention, the medicine is used to treat immunodefiiciency disease.Thus, according to present invention implementation
The preparation of example can be effectively facilitated activated immune cell, activating immune system, so as to play treatment immunodefiiciency disease
Effect.
Embodiments in accordance with the present invention, the cell of the secretion Interleukin 25 is keratinocyte.Inventor's discovery, angle
Matter formation cell is the main source of Interleukin 25.Thus, preparation according to embodiments of the present invention can be effectively facilitated immune
Cell activation, activating immune system.
The method of immune cell activated
In still another aspect of the invention, the present invention proposes a kind of method of immune cell activated.According to the reality of the present invention
Example is applied, methods described includes：Immunocyte is set to be contacted with selected from least one of following：(a) Interleukin 25 or its function are similar
Thing；(b) secretion Interleukin 25 or the cell of its functional analogue；(c) Interleukin 25 activator or its analog；(d)IL-17RB
Or its functional analogue；(e) IL-17RB activators or its functional analogue；(f) STAT3 or its functional analogue；(g) it is white to be situated between
Element 17 or its functional analogue；And the expression accelerator of any one of (h) (a)~(g).Thus, it is according to embodiments of the present invention
Method being capable of effectively immune cell activated.
It will be appreciated to those of skill in the art that above for the feature described by purposes of the preparation in medicine is prepared
And advantage, the method for being equally applicable to the immune cell activated, it will not be repeated here.
Suppress the method for immune cell activation
In still another aspect of the invention, the present invention proposes a kind of method for suppressing immune cell activation.According to the present invention
Embodiment, methods described includes：Immunocyte is set to be contacted with selected from least one of following：(1) Interleukin 25 antagonist or
Its functional analogue；(2) IL-17RB antagonists or its functional analogue；(3) STAT3 antagonists or its functional analogue；(4)
Interleukin-17 antagonist or its functional analogue；And (5) Interleukin 25, IL-17RB, interleukin-17 or STAT3 expression
Inhibitor.Thus, method according to embodiments of the present invention can effectively suppress immune cell activation.
It will be appreciated to those of skill in the art that above for the feature described by purposes of the reagent in medicine is prepared
And advantage, the method for being equally applicable to the suppression immune cell activation, it will not be repeated here.
Vaccine
In still another aspect of the invention, the present invention proposes a kind of vaccine.Embodiments in accordance with the present invention, the vaccine contains
There is antigen and selected from least one of following：(a) Interleukin 25 or its functional analogue；(b) secretion Interleukin 25 or its work(
The cell of energy analog；(c) Interleukin 25 activator or its analog；(d) IL-17RB or its functional analogue；(e)IL-
17RB activators or its functional analogue；(f) STAT3 or its functional analogue；(g) interleukin-17 or its functional analogue；With
And the expression accelerator of any one of (h) (a)~(g).Thus, method according to embodiments of the present invention can be effectively facilitated immune
Cell activation, so that activating immune system, produces corresponding antibody.
It will be appreciated to those of skill in the art that above for the feature described by purposes of the preparation in medicine is prepared
And advantage, the vaccine is equally applicable to, be will not be repeated here.
The method for screening medicine
In still another aspect of the invention, the present invention proposes a kind of method for screening medicine.Embodiments in accordance with the present invention,
Methods described includes：By candidate agent and cells contacting, the cell secretes Interleukin 25；And before and after the determination contact,
The Interleukin 25 expression of the cell, wherein, the Interleukin 25 expression rise, is the candidate agent after the contact
It is used as the instruction of immunodefiiciency disease medicine；The Interleukin 25 expression reduction after the contact, is that the candidate agent is made
For the instruction of autoimmune disease medicine.
As it was previously stated, the high expression of Interleukin 25 can promote activated immune cell, and then activating immune system, play pre-
Anti- and treatment immunodefiiciency disease effect；Interleukin 25 expression, which is suppressed, can suppress activated immune cell, and then suppress to exempt from
Epidemic disease system, plays the effect of prevention and treatment autoimmune disease.Thus, screening medicine according to embodiments of the present invention is utilized
Method result in autoimmune disease medicine or immune activation medicine.
It should be noted that " cell secretion Interleukin 25 " should broadly understood, being primarily referred to as the cell can secrete white
Interleukin 25 or the potential with secretion Interleukin 25.According to a particular embodiment of the invention, the cell is that cutin is formed carefully
Born of the same parents.
The solution of the present invention is explained below in conjunction with embodiment.It will be understood to those of skill in the art that following
Embodiment is merely to illustrate the present invention, and should not be taken as limiting the scope of the invention.Unreceipted particular technique or bar in embodiment
Part, carried out according to the technology or condition described by document in the art or according to product description.Agents useful for same or instrument
The unreceipted production firm person of device, being can be by the conventional products of acquisition purchased in market.
Embodiment 1
In order to study effect of the Interleukin 25 in psoriasis, the table of the Interleukin 25 in psoriasis patients is have detected first
Reach.Compared with the skin of normal patient, the expression of the Interleukin 25 in psoriasis patients skin has in mRNA and protein level
Significantly rise.IMQ is a kind of a kind of medicine for being commonly used to induce psoriatic phenotype with mouse, is established using this method small
Mouse psoriasis model, in mouse skin, Interleukin 25 is in mRNA and the high expression of protein level.
In order to further explore 25 effect, using the albumen of direct injection Interleukin 25 in skin.In a period of time
Injection after, cutaneous manifestations go out the feature of similar psoriasis, include the hyper-proliferative of epidermis, the infiltration of dermal inflammation cell.
What is more important, the injection of Interleukin 25 significantly improve in skin Interleukin 25 in itself and its acceptor expression,
Also include interleukin-17, interleukin-17 C expression, and interleukin-17 and 17C are it is verified that in psoriasis growth course
Play an important role.
More than data imply that Interleukin 25 possible important function in the growth course of psoriasis.In order to further
This effect of confirmation, induction of IMQ psoriasis models on the mouse that Interleukin 25 is lacked, as a result as depicted in figs. 1 and 2.Fig. 1
In, A：Gene expression of the Interleukin 25 in normal skin and psoriatic；B：Interleukin 25 is in normal and psoriatic
Immunofluorescence dyeing in skin paraffin section；C：Interleukin 25 mRNA in the mouse skin of normal and imiquimod processing
The expression of level；D：The immunofluorescence dye of Interleukin 25 in the treated mouse skin section of normal mouse skin and IMQ
Color；E：The C57BL/6 mouse backs skin injected respectively with pbs (n=5) or IL-25 (n=5) then carries out color；F：Use pbs
(n=5) or IL-25 (n=5) inject C57BL/6 mouse ear, progress H＆E dyeing；G：With pbs (n=5) or IL-25 (n
=C57BL/6 mouse ears 5) are injected, mouse ear thickness is tested daily；H：With after PBS or IL-25 injection mouse skins two
The expression change of portion gene between group.Experimental result in triplicate, as a result unanimously.Engineer's scale represents 100 μm in (B) and (D),
Represented in (E) and (F) 50 μm (enlarged drawings) or 100 μm (reducing figure).*P<0.05, * * P<0.01；N.s., without difference, p
Value determines that data are represented in the form of the positive and negative mark of average value is missed with t-test.
In Fig. 2, A：Wild-type mice and Interleukin 25 knock out mice smear IMQ (imiquimod) to induce silver respectively
Bits disease, continues to be for 3.5 days H＆E and dye and do epidermis and dermis thickness statistics.Meanwhile, separate dermal cell and do flow cytometer showed marrow
Be cell proportion, i.e. ratio of the CD45+ cells in each group (see B)；C：Analyze corium myeloid cell and analyze thin in CD45+ simultaneously
The ratio change of all kinds cell in born of the same parents.Experimental result in triplicate, as a result unanimously.Engineer's scale represents 50 μm；*P<
0.05, * * P<0.01；N.s., without difference, p value is determined with t-test, and data are come in the form of the positive and negative mark of average value is missed
Represent.
As a result show, the order of severity of the psoriatic phenotype of this mouse to be much lighter than wild type induction of psoriasis
The quantity and ratio of immunocyte will also be far below the mouse of wild type in the mouse of model, and this mouse skin.Corium
The immunocyte of middle reduction includes BMDC, macrophage and gamma delta T cells.Except neutrophil leucocyte ratio relative to
Wild type, which has, slightly to be risen, and the ratio and total cell number of these cells have obvious decline both relative to wild type.Meanwhile, in vain
The missing of interleukin 25 also results in such as interleukin-17,22,6,23 mrna expression amount and decline.
In a word, data above shows that Interleukin 25 plays an important role during the genesis and development of psoriasis really.
Embodiment 2
The data of immunofluorescence demonstrate Interleukin 25 only has expression in the epidermis of psoriatic skin, implys that cutin shape
It is probably the main source of Interleukin 25 into cell.Due to lacking support sample acceptor 7/8, keratinocyte can not be directly to IMQ
Make a response.In order to confirm how Interleukin 25 is reached by initiate table in skin, keratinocyte has been cultivated in vitro
And with different it is verified that the effective factor goes to stimulate these cells to detect interleukin in psoriasis generating process
The situation that 25 expression is induced, these factors include interleukin-17,17C and TNF-α etc..As a result it is as shown in Figure 3.Wherein A：
In vitro culture keratinocyte and the situation for going to stimulate the expression to detect Interleukin 25 to be induced with different cell factors；
B and C：In psoriasis model, no matter the expression of Interleukin 25 is in the depleted mice of interleukin-17 in mRNA level in-site or egg
White level is all decreased significantly.Experimental result in triplicate, as a result unanimously.Engineer's scale represents 100 μm, * P in (C)<
0.05, * * P<0.01；N.s., without difference, p value is determined with t-test, and data are come in the form of the positive and negative mark of average value is missed
Represent.
As a result show, among these factors, only interleukin-17 can significantly induce the expression of Interleukin 25.And it is white
The missing of interleukin 17 causes the expression of the Interleukin 25 in psoriasis model no matter having aobvious in mRNA level in-site or protein level
Write and decline.Therefore, Interleukin 25 may in the pathogenic process of psoriasis as interleukin-17 an important downstream elements.
Embodiment 3
Because the expression of Interleukin 25 is mainly limited to high hyperplasia keratinocyte in the injured skin of psoriasis people,
So as to assume that the Interleukin 25 expressed in keratinocyte can promote the development of psoriasis.Fig. 4 indicates cutin and formed carefully
Specific Interleukin 25, which is knocked out, in born of the same parents make it that psoriasis symptom declines in mouse.Wherein, A：Wild-type mice and Interleukin 25
Specific skin epidermal cell knock out mice (IL-25f/fK5Cre) smears IMQ (imiquimod) to induce silver-colored bits respectively
Disease, continues to be for 3.5 days H＆E and dyes and do epidermis counting with dermis thickness, meanwhile, separation dermal cell simultaneously does flow cytometer showed medullary system
The ratio of cell proportion, i.e. CD45+ cells in each group (see figure B)；C：Analyze corium myeloid cell and analyze thin in CD45+ simultaneously
The ratio change of all kinds cell in born of the same parents.Experimental result in triplicate, as a result unanimously.Engineer's scale represents 50 μm；*P<
0.05, * * P<0.01；N.s., without difference, p value is determined with t-test, and data are come in the form of the positive and negative mark of average value is missed
Represent.
The floxed mouse of Interleukin 25 gene (Il25) can select with the hybridization of K5Cre DNA murines in keratinocyte
Selecting property removes the Il25 expression of keratinocyte.Il25 expression is small in the small Il25f/fk5Cre induction of psoriasis model
Mouse induces compared to IMQ and substantially reduced in WT mouse skin damageds.Similar to Il25 germ line gene knock-out mices, Interleukin 25 is in cutin
The shortage formed in cell substantially reduces epidermis prickle cell's hyperplasia, dermis thickness and the infiltration of skin corium immunocyte.In addition, dendron
Shape cell (CD45+、CD11c+), neutrophil leucocyte (CD45+、CD3-、CD11b+、Gr1+) and delta T cells (CD45+、CD3+、δT+)
Number and percentage all reductions, but compared with Il25f/fK5Cre psoriasis model mouse, in Il25f/f groups, macrophage
The quantity of cell (CD45+CD3-CD11b+F4/80+) is not significantly reduced.These as shown by data, epidermal keratinocytes production
Raw Interleukin-25 can as driving psoriasis pathological development main source.
Embodiment 4
Interleukin-25 to interleukin-2-receptor composite I L17RB and IL17RA can be applied to body by target
Immune and nonimmune cell.In order to confirm that Interleukin 25, how by the IL 17RB of activation activity, uses recombination leukocyte first
Interleukin 25 stimulates mouse keratinocyte.As a result it is as shown in Figure 5.Wherein, A：Culture keratinocyte is used in combination in vitro
Interleukin 25 goes to stimulate to detect the expression of Interleukin 25 and its acceptor IL-17RB；B：Wild-type mice and Interleukin 25 gene
Receptor knockout mice smears IMQ (imiquimod) to induce psoriasis respectively, continue to be for 3.5 days H＆E dye and do epidermis with it is true
Skin thickness is counted, meanwhile, separate dermal cell and do flow cytometer showed myeloid cell ratio, i.e. CD45+Ratio of the cell in each group
Example (see figure C)；D：The mRNA level in-site of the psoriasis model skin for the mouse that analysis Interleukin 25 acceptor is knocked out in Interleukin 25
Expression.Experimental result in triplicate, as a result unanimously.Engineer's scale represents 50 μm；*P<0.05, * * P<0.01；N.s., without difference.
P value determines that data are represented in the form of the positive and negative mark of average value is missed with t-test.
The stimulation of Interleukin-25 greatly enhances the expression (figure of Il17rb and Il25 in primary keratinocyte
5A).Next, using Il17rb/-Mouse psoriasis model, it is found that psoriasis pathology induces Il17rb in IMQ-/-Mouse in
Mitigate (Fig. 5 B) significantly.In addition, it was further observed that IL 17RB expression greatly reduce in the epidermis of Il25 deficient mices (Fig. 5 C,
5D).In order to further assess the target cell of Interleukin 25 in psoriasis model, bone marrow neoplasms experiment is carried out, from bone marrow cell
The WT and Il17rb of separation/-Mouse is transferred to respectively is irradiated WT or Il17rb by lethal dose-/-Mouse, after 8 weeks, is lured by mouse with IMQ
Send out psoriasis.Il17rb-/-Recipient mice has a psoriasiform symptom being relieved, and Il17rb-/-Donor bone marrow cell then
Without this phenotype (Fig. 5 E).In summary, Interleukin 25 regulation is largely that silver-colored bits are adjusted by targetting non-hematopoietic cell
The generation of disease, and be likely to be the form by autocrine.
Embodiment 5
In order to determine the function downstream elements of keratinocyte in Interleukin 25, cutin is stimulated to be formed carefully with Interleukin 25
Born of the same parents 8 hours, the gene mRNA situation for the technique study Interleukin 25 regulation being then sequenced with RNA.Generally, in Interleukin 25
Under stimulation, 8,449 kinds of gene expression up-regulations, 7,272 kinds of down regulation of gene expression.In the gene that interleukin 25 is induced, wherein
There are substantial amounts of chemotactic factor (CF) and cell factor to attract or induce various psoriasis associated immune cells into skin, including
CCL2 can recruit monocyte, T cell and BMDC, and CCL7 can recruit monocyte, monocyte and T cell,
CX3CL1 and CSF3 can stimulate grain system hematopoietic cell.The controllable in addition, gene of many Interleukin-25 inductions is once reported
Cell is bred and cell cycle progression, including Ccl2, Fn1.
Therefore, Interleukin 25 may promote psoriasis to develop by adjusting cell propagation and induction inflammation gene expression.In order to
It is further to be confirmed, keratinocyte is stimulated in vitro with Interleukin-25.Specifically, angle is separately cultured from mouse
Matter formation cell simultaneously stimulates 8h with Interleukin 25, using culture medium as control, extracts RNA and does express spectra sequencing detection.As a result such as
Shown in Fig. 6.Wherein, A：The analysis of the difference expression gene signal path adjusted to Interleukin 25；B：The base of Interleukin 25 regulation
The scatter diagram of cause；C：Primary culture keratinocytes Interleukin 25 or culture medium are stimulated calculates thin in various concentrations and time point
Born of the same parents' number changes；E：Culture mouse skin horn cell simultaneously is gone to stimulate with Interleukin 25, and 48h after stains ki67 goes to see that cell breeds shape
State；F：Culture mouse skin horn cell is gone to stimulate with Interleukin 25, and 24h after stains DAPI sees that the cell cycle changes；G：Wild
Ki67 immunofluorescence dyeing (10X) is done in the mouse skin of type and Interleukin 25 missing；Engineer's scale represents 50 μm；*P<
0.05.**P<0.01；N.s., without difference.P value is determined with t-test.Data are come in the form of the positive and negative mark of average value is missed
Represent.
It was found that time point (Fig. 6 D) of the Interleukin 25 after relatively promotes cell to increase in dose-dependent mode (Fig. 6 C)
Grow raising cell quantity.Similarly, Interleukin 25 also improves proliferation marker Ki67 expression ratio (Fig. 6 E), and has more
Cell enters the active cell cycle (S and G2/M phases) (Fig. 6 F).On the contrary, Il25 missings greatly reduce the mouse skin of induction psoriasis
The Ki67 of skin epidermis histochemical staining ratio and quantity (Fig. 6 G and Fig. 6 A), further demonstrates that Interleukin 25 in regulation cutin shape
Into the essential effect of propagation of the cell in onset of psoriasis.
Embodiment 6
The signal transduction mechanism that Interleukin 25 mediation keratinocyte proliferation and inflammatory factor are produced will be studied herein.This
Preceding known Act1 is as adaptor protein, the signal path of mediated leucocytes interleukin 25, and we compare WT and Act1/- mouse cutin
The related gene expression for forming several Interleukin 25 mediations in cell is bred or or the gene relevant with inflammatory reaction with cell.Knot
Fruit is as shown in Figure 7.Wherein, A：Stimulated or do not stimulated with Interleukin 25 in the keratinocyte that wild type and ACT1 are lacked
8h, observes the induced expression situation by the RNAseq genes picked out；B：The keratinocyte lacked in wild type and ACT1
In, stimulated with Interleukin 25 or do not stimulate 24h to go to see that cell proliferation marker ki67 (left side) and cell cycle (right side) change；C：
Keratinocyte is stimulated or 24 hours with Interleukin 25, Phosphorylation status of the observation stat3 in two groups；D：Phosphorylation
STAT3 (p-stat3) is with PBS or by the SABC in the skin that Interleukin 25 injects after inducing 16 days；E：Cutin
Forming cell is stimulated with Interleukin 25 or does not stimulate 24h, in STAT3 phosphorylation inhibitors or the processing of interleukin 6 antibody or
It is the ki67 and cell cycle analysis in the case of not handling；F：Keratinocyte with Interleukin 25 stimulate or do not stimulate or
It is after the inhibitors of phosphatases plus STAT3 and after handling 8h, to observe the expression of select RNA seq related genes
Change.Engineer's scale represents 50 μm；*P<0.05, * * P<0.01；N.s., without difference.P value is determined with t-test.Data are with flat
The form that the positive and negative mark of average is missed is represented.
Act1 missing can make the stimulation of Interleukin 25 disappear.In addition, as may be expected, by Interleukin 25
The keratinocyte proliferation of induction depends on Act1 (Fig. 7 B).
STAT3 is well known in the factor that cell cycle and cell propagation are controlled in different cells, including angle
Matter formation cell, and have been demonstrated that psoriasiform scytitis can be participated in.In order to determine it is logical whether Interleukin 25 can be adjusted
Overactivation STAT3 adjusts keratinocyte proliferation, and we test keratinocyte under the stimulation of Interleukin 25
STAT3 phosphorylation.As a result show, the stimulation of Interleukin 25 result in obvious STAT3 phosphorylations (Fig. 7 C) in 24 hours.
Similarly, injection of skin Interleukin-25 also induces obvious STAT3 phosphorylations (Fig. 7 D).In addition, blocking STAT3 activation
STAT3 inhibitor sttatic substantially reduces keratinocyte proliferation and the cell cycle change of Interleukin-25 induction,
And this process is independently of (Fig. 7 E) of the effect of interleukin-6.It has been found that related to keratinocyte proliferation
Gene expression or to recruiting in the related gene of inflammatory cell, such as Ccl2, Ccl7 and Csf3, depending on STAT3 activation, and
Other genes, such as Naip5 and Dclre1c, then independent STAT3 activation (Fig. 7 F).In a word, Act1 and STAT3 signals for
The expression of Interleukin 25 induction keratinocyte proliferation and cell factor and chemotactic factor (CF) is very important.
Embodiment 7
Above-mentioned as shown by data, the mitosis influence of Interleukin 25 Human Keratinocytes relies on STAT3 activation but only
The signal (Fig. 7 E and 7F) of vertical interleukin-6 mediation, thus, prediction Interleukin 25 can directly activate STAT3.In order to examine
This possibility, with Interleukin 25 stimulated in vitro keratinocyte, carry out in the short period of time the detection of STAT3 activation with
It is two grades of effects to exclude this effect.Fig. 8 indicates Interleukin 25 and can activate adaptor protein ACT1 and STAT3 to play in cutin
The function of being formed on cell.Wherein, A：The primary angle separated in stimulating the suckling mouse lacked from wild type and ACT1 with Interleukin 25
Matter formation cell, collects cell in different time points and does immunoblot experiment, study p-Stat3 and Stat3 albumen table
Reach；B：Wild type keratinocyte is stimulated with Interleukin 25, interleukin 6 neutralizing antibody or JAK1/2 inhibitor processing or
Person does not study p-Stat3 and Stat3 expression under disposition；C：In 293T cells be overexpressed HA labels Interleukin 25 by
Body IL-17RB and STAT3 or empty plasmid and STAT3, collect cell and crack, co-immunoprecipitation IL-17RB, then Western blotting
STAT3 and HA labels；D：The Interleukin 25 acceptor IL-17RB of HA labels is overexpressed in 293T cells, different time points are used
Interleukin 25 is stimulated, and collects cellular immunity co-precipitation HA label proteins, and Western blotting tyrosine phosphorylation antibody and HA labels are anti-
Body；E：Cultivate mouse primary keratinocyte is stimulated one hour with Interleukin 25, with another acceptor IL- of receptor interleukin 25
17RA carries out co-immunoprecipitation, Western blotting IL-17RA and STAT3.
Consistent with Function detection (Fig. 7 E) result, Interleukin 25 induces obvious STAT3 phosphorylations, and this after 10 minutes
Process depends on Act1, but is independently of interleukin-6.Also, it is this to act on JAK1/2 inhibitor such as report
It is wholly absent under processing (Fig. 8 A, 8B).This result shows that STAT3 may directly be activated by Interleukin 25.Next we
Whether the IL-17RB marked in 293T cells with HA examines STAT3 can be with IL-17RB direct interactions.Have been surprisingly found that,
STAT3 (Fig. 8 C) is detected in the albumen composition containing IL-17RB after immunoprecipitation.In addition, Interleukin 25 can be at 10 minutes
The tyrosine phosphorylation (Fig. 8 D) on IL17RB is induced afterwards.Because Interleukin 25 is answered by being attached to IL-17RA/IL-17RB
Compound acceptor carries out downstream signal transduction, we study the Interleukin-25 in the mouse keratinocyte stimulation whether
IL-17RA/RB compounds and STAT3 interaction can be promoted.Endogenous leukocyte interleukin -17RA is found and stat3 bases
Because of co-precipitation (Fig. 8 E).In summary, result of study is that Interleukin 25 can directly activate STAT3 in keratinocyte
Phosphorylation provide experimental evidence.
In the description of this specification, reference term " one embodiment ", " some embodiments ", " example ", " specifically show
The description of example " or " some examples " etc. means to combine specific features, structure, material or the spy that the embodiment or example are described
Point is contained at least one embodiment of the present invention or example.In this manual, to the schematic representation of above-mentioned term not
Identical embodiment or example must be directed to.Moreover, specific features, structure, material or the feature of description can be with office
Combined in an appropriate manner in one or more embodiments or example.In addition, in the case of not conflicting, the skill of this area
Art personnel can be tied the not be the same as Example or the feature of example and non-be the same as Example or example described in this specification
Close and combine.
Although embodiments of the invention have been shown and described above, it is to be understood that above-described embodiment is example
Property, it is impossible to limitation of the present invention is interpreted as, one of ordinary skill in the art within the scope of the invention can be to above-mentioned
Embodiment is changed, changed, replacing and modification.
Claims (10)
1. purposes of the reagent in medicine is prepared, it is characterised in that the medicine is used to suppress immune system activation, the reagent
Selected from least one of following：
(1) Interleukin 25 antagonist or its functional analogue；
(2) IL-17RB antagonists or its functional analogue；
(3) STAT3 antagonists or its functional analogue；
(4) interleukin-17 antagonist or its functional analogue；And
(5) Interleukin 25, IL-17RB, interleukin-17 or STAT3 expression inhibiting agent.
2. purposes according to claim 1, it is characterised in that the medicine is used to treat autoimmune disease.
3. purposes according to claim 1, it is characterised in that the medicine is used to treat psoriasis.
4. purposes of the preparation in medicine is prepared, it is characterised in that the medicine is used for activating immune system, the preparation is selected from
It is at least one of following：
(a) Interleukin 25 or its functional analogue；
(b) secretion Interleukin 25 or the cell of its functional analogue；
(c) Interleukin 25 activator or its analog；
(d) IL-17RB or its functional analogue；
(e) IL-17RB activators or its functional analogue；
(f) STAT3 or its functional analogue；
(g) interleukin-17 or its functional analogue；And
(h) any one of (a)~(g) expression accelerator.
5. purposes according to claim 4, it is characterised in that the medicine is used to treat immunodefiiciency disease.
6. purposes according to claim 4, it is characterised in that the cell of the secretion Interleukin 25 is that cutin is formed carefully
Born of the same parents.
7. a kind of method of immune cell activated, it is characterised in that including：
Immunocyte is set to be contacted with selected from least one of following：
(a) Interleukin 25 or its functional analogue；
(b) secretion Interleukin 25 or the cell of its functional analogue；
(c) Interleukin 25 activator or its analog；
(d) IL-17RB or its functional analogue；
(e) IL-17RB activators or its functional analogue；
(f) STAT3 or its functional analogue；
(g) interleukin-17 or its functional analogue；And
(h) any one of (a)~(g) expression accelerator.
8. a kind of method for suppressing immune cell activation, it is characterised in that including：
Immunocyte is set to be contacted with selected from least one of following：
(1) Interleukin 25 antagonist or its functional analogue；
(2) IL-17RB antagonists or its functional analogue；
(3) STAT3 antagonists or its functional analogue；
(4) interleukin-17 antagonist or its functional analogue；And
(5) Interleukin 25, IL-17RB, interleukin-17 or STAT3 expression inhibiting agent.
9. a kind of vaccine, it is characterised in that containing antigen and selected from least one of following：
(a) Interleukin 25 or its functional analogue；
(b) secretion Interleukin 25 or the cell of its functional analogue；
(c) Interleukin 25 activator or its analog；
(d) IL-17RB or its functional analogue；
(e) IL-17RB activators or its functional analogue；
(f) STAT3 or its functional analogue；
(g) interleukin-17 or its functional analogue；And
(h) any one of (a)~(g) expression accelerator.
10. a kind of method for screening medicine, it is characterised in that including：
By candidate agent and cells contacting, the cell secretes Interleukin 25；And
Before and after determining the contact, the Interleukin 25 expression of the cell,
Wherein, the Interleukin 25 expression rise after the contact is the candidate agent as immunodefiiciency disease medicine
Instruction；
The Interleukin 25 expression reduction, is finger of the candidate agent as autoimmune disease medicine after the contact
Show.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016049000A2 (en) * | 2014-09-23 | 2016-03-31 | Regeneron Pharmaceuticals, Inc. | Anti-il-25 antibodies and uses thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016049000A2 (en) * | 2014-09-23 | 2016-03-31 | Regeneron Pharmaceuticals, Inc. | Anti-il-25 antibodies and uses thereof |
Non-Patent Citations (3)
| Title |
|---|
| 姚煦: "特应性皮炎的发病机制", 《医学与哲学》 * |
| 王娅等: "银屑病转基因动物模型研究进展", 《中国药理学通报》 * |
| 王茹等: "白细胞介素 17 与疾病关系的研究进展", 《医学综述》 * |
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