CN103751803A - Interferon regulatory factor 9 (IRF9) and application of inhibitor thereof in cerebral apoplexy - Google Patents

Abstract

The invention discloses interferon regulatory factor 9 (IRF9) and application of an inhibitor thereof in cerebral apoplexy, belonging to the field of gene function and application. The invention uses IRF9 gene knock-out mice and brain-specific IRF9 transgenic mice as experimental subjects and adopts middle cerebral artery ischemia reperfusion model, results show that compared with mild type C57 mouse, the brain infarction volume of IRF9 gene knock-out mouse is apparently inhibited, and nerve function is improve remarkably, while the infarction volume of nerve-specific IRF9 transgenic mouse is apparently inhibited, and nerve function is deteriorated markedly. Therefore, IRF9 gene has nervous system function deterioration effect; especially, IRF9 gene can deteriorate cerebral apoplexy. As for the above function of IRF9, the invention provides application of IRF9 as drug target of cerebral apoplexy treatment in developing medicaments for treating cerebral apoplexy.

Description

Interferon regulatory factor 9 (IRF9) and the application of inhibitor in apoplexy disease thereof

Technical field

The invention belongs to function and the application of gene, particularly a kind of interferon regulatory factor interferon regulatory factor 9(IRF9) and the application of inhibitor in apoplexy disease.

Background technology

Cerebral infarction is global the fourth-largest lethal factor and second largest disability-causing factor at present, occurs irreversible brain injury patient's life and health being caused to serious harm after it in several minutes to a few hours.Neuronal cell is the important ingredient of central nervous system, but its high metabolic rate reduced hypoxic-ischemic environment tolerance, therefore compared with other neural blood vessel element components, is more vulnerable to damage.The treatment of at present tissue plasminogen activator (tPA) fibrinolytic is still the primary treatment means of cerebral infarction, but its only the time window of 4.5 little durations limit most of patient and can only accept symptomatic treatment.Research shows, neuro-protective strategy can improve brain function after cerebral ischemia in the long period, reduces neuronal cell loss.Apoptosis is one of fundamental mechanism of cell death in cerebrum ischemia/refilling process, but its regulatory mechanism is illustrated not yet completely.Therefore, during research cerebrum ischemia/pour into again, the molecular mechanism of neuronal cell apoptosis existence, provides new therapeutic strategy and method by contributing to for neuro-protective.

Most research thinks, recovers cerebral tissue blood supply and be the effective method for the treatment of cerebral ischemia.Although 1996 Nian Qi tissue plasminogen activators (tPA) ratify for cerebral infarction treatment, it remains the thrombolytic drug that the unique audit of U.S. Bureau of Drugs Supervision (FDA) is passed through up to now.Because extend in time bleeding risk, increase, the therapeutic time window of tPA is only 4.5 hours; Consider the difficult discriminating of iconography in early days of ischemic and hemorrhagic apoplexy, further incured loss through delay patient and accepted the chance that tPA treats.Only be less than at present 5% ischemic cerebral stroke patients use tPA thromboembolism treatment.In addition, if the long-time severe ischemic anoxia of cerebral tissue is found in research, even recover cerebral blood flow in the later stage, still can cause irreversible damage to cerebral tissue, therefore current still in the urgent need to studying the therapeutic strategy of the pathophysiology event for hypoxic-ischemic and (or) due to pouring into again.Since the nineties in 20th century, the therapeutic strategy of research neuroprotective and cerebral tissue is the focus of Treatment of Cerebral Stroke always, and these strategies not only can extend the therapeutic time window of tPA, also can alleviate the brain tissue impairment of ischemia-reperfusion induction.Multiple nerve protection medicine has been obtained stem-winding result in zoopery; but enter after apoplexy 3 phase clinical experiment; overwhelming majority medicine does not all attain the results expected; one of its primary failed reason is that most of known Neuroprotective Mechanisms acted on after apoplexy in 4-6 hour; and in clinical practice, be difficult to implement treatment in so of short duration time window, after therefore further illustrating apoplexy and occurring, in longer a period of time, promote or the molecular mechanism of protection brain tissue impairment significant for the effective Treatment of Stroke target spot of research or strategy.

Interferon regulatory factor (interferon regulatory factor, IRF) family has had now found that 10 members, and it consists of IRF1～IRF10.Existing research prompting, IRF family member has participated in biological process widely, relates generally to the natural immunity and the acquired immune response, and regulating cell growth and existence, apoptosis and propagation participate in hemopoietic, antitumor formation etc.IRF9 is called again P48, the interferon-stimulated gene factor (IFN-stimulated gene factor 3 γ, ISGF3 γ).Have at present the research of IRF9 mainly to concentrate on antiviral, IRF-9 and HBV IFN-stimulated response element spline structure territory in conjunction with after, it expresses rapid rise and can strengthen the remarkable inhibition of the HBV mRNA level of IFN-α induction.Have recently report, mice, after IRF9 gene knockout (Knockout, KO), shows as the T cell and the neutrophilic granulocyte number that increase in intestinal mucus and lymph node, and this prompting IRF9 and inflammation have close ties.(Lohoff M etc., Nature reviews Immunology. 2005; 5 (2): 125-35; Honda K etc., Nature reviews Immunology. 2006; 6 (9): 644-58.)

Summary of the invention

For solving defect and the deficiency of above-mentioned prior art, primary and foremost purpose of the present invention is to provide a kind of IRF9 to apply in the medicine of screening treatment apoplexy disease as drug targets.

Another object of the present invention is to provide the inhibitor of a kind of IRF9 to treat the application in apoplexy disease medicament in preparation.

Object of the present invention is achieved through the following technical solutions:

The present invention is take IRF9 knock out mice and Neuron-specific IRF9 transgenic mice as experimental subject, by Cell transplantation model, result shows to contrast with wild type C57 mice, IRF9 knock out mice cerebral infarction is obviously suppressed, function of nervous system is also clearly better, the Infarction volume of Neuron-specific IRF9 transgenic mice obviously increases, and function of nervous system obviously worsens.This prompting IRF9 gene has the effect that worsens nervous function, can worsen the nerve injury that cerebral ischemia causes, for novel targets and the New Policy of research control cerebral ischemia provide theoretical foundation and Clinical Basis.

For the above-mentioned functions of IRF9, provide a kind of IRF9 to apply in the medicine of screening treatment apoplexy disease as drug targets.

For the above-mentioned functions of IRF9, provide the inhibitor of a kind of IRF9 to apply in preparation treatment apoplexy disease medicament.

A medicine for the treatment of apoplexy disease, comprises IRF9.

The inhibitor of described IRF9 is the one in siRNA, the rna interference vector of IRF9 gene or the antibody of IRF9 of IRF9 gene.

The present invention has following advantage and effect with respect to prior art:

1. the present invention finds the new function of IRF9 gene, and IRF9 gene can worsen the effect of apoplexy disease.

2.IRF9, in the effect worsening in apoplexy disease, is the drug provision target of development apoplexy disease.

Accompanying drawing explanation

Fig. 1 is structure and the qualification result figure of nerve-specific IRF9 transgenic mice

A is the design of graphics of nerve-specific IRF9 transgenic mice;

B is the qualification result figure of nerve-specific IRF9 transgenic mice;

Fig. 2 is the TTC coloration result figure of WT and IRF9-KO mice.

A is TTC coloration result figure;

B is cerebral infarction volume statistics block diagram;

C is function of nervous system's scoring statistics block diagram;

Fig. 3 is the TTC coloration result figure of IRF9-TG and NTG mice.

A is TTC coloration result figure;

B is cerebral infarction volume statistics block diagram;

C is function of nervous system's scoring statistics block diagram;

Fig. 4 is cerebral tissue infarction surrounding zone neuronal cell apoptosis situation measurement result figure.

Figure A is Fluoro Jade B and TUNEL apoptosis detection display figure;

Figure B is the statistical result figure that figure A Fluoro Jade B and TUNEL apoptosis detect;

The specific embodiment

Below in conjunction with embodiment and accompanying drawing, the present invention is described in further detail, but embodiments of the present invention are not limited to this.

Animal for research and raising

Laboratory animal: select age in 11-12 week, body weight at 25-30g; background is the wild-type mice (WT of male C57BL/6 strain; purchased from China bio tech ltd, Fukang, Beijing; 949431), IRF9 knock out mice (IRF9-KO the certification of fitness number:; C57BL/6J background; purchase is from RIKEN BRC company (BRC numbering: RBRC00916)), non-transgenic mice (NTG, Neuron-specific Cre transgenic mice (CaMKII α-Cre; Purchased from Jackson Laboratory, Stock No. 005359)) and nerve-specific IRF9 transgenic mice (IRF9-TG, by IRF9-flox mice and the hybridization of CaMKII α-Cre mice, obtained, IRF9-flox mice is built by the Li Hongliang of angiocardiopathy institute of Wuhan University professor laboratory, and the building process of IRF9-flox mice as described hereinafter).

Feeding environment: all experiment mices are all raised in the SPF of Wuhan University angiocardiopathy institute level Experimental Animal Center.Mice special feed is provided by Chinese military medicine academy of science animal center.Raising condition: room temperature is between 22-24 ℃, and humidity is between 40-70%, and it is 12h that light and shade replaces lighting hours, freely drinks water and ingests.

The structure of [embodiment 1] nerve-specific IRF9 transgenic mice

The building process of IRF9-flox mice:

Transgene carrier builds information: with forward primer, i.e. 5 '-CCAGATTACGCTGATATGGCATCAGGCAGGGCACG-3 ' (SEQ ID NO. 1), downstream primer, 5 '-AGGGAAGATCTTGATTCAGCAGGCTCTACACAGGG-3 ' (SEQ ID NO. 2), amplification mice IRF9 full-length gene (NCBI, Gene ID:16391, NM_001159417.1), cDNA is inserted to pCAG-CAT-LacZ carrier, β-actin gene (CAG that this carrier comprises a cmv enhancer and a chicken, chicken β-actin gene) promoter, and be connected to chloramphenicol acetyl transferasegene (CAT, chloramphenicol acetyltransferase), loxP site is positioned at CAT both sides, the expression of neurocyte IRF9 obtains (Figure 1A) by CAG promoters driven.IRF9-floxed mice: the pCAG-IRF9-CAT-LacZ carrier of structure, by the microinjection embryo's (C57BL/6J background) that is configured to be fertilized, is obtained to IRF9-floxed mice.Neuronal specificity IRF9 transgenic mice obtains by IRF9-flox mice and CaMKII α-Cre mice (non-transgenic mice NTG) outbreeding.

Transgenic mice is got genomic DNA by cutting tail, use PCR to identify, PCR identifies that primer information is: detect forward primer 5 '-CCAGATTACGCTGATTGTGACCGGAACGGCGGGCG-3 ' (SEQ ID NO. 3), detect reverse primer 5 '-AGGGAAGATCTTGATTTAGACGGTGATCTGTTGAT-3 ' (SEQ ID NO. 4).By the expression of IRF9 albumen in the different transgenic mouse heads of western blotting (Western Blot) experimental identification: extract different transgenic mouse cerebral tissue albumen, by polyacrylamide gel electrophoresis (SDS-PAGE), checking IRF9 crosses expression (Figure 1B).

For further studying IRF9, cross the impact of expressing for cerebral ischemia/reperfusion injury, we have built a few strain nerve-specific IRF9 transgenic mices (IRF9-TG).In order to reflect the change of IRF9 under pathological and physiological condition, we have selected IRF9-TG3 mice, Western Blot and quantitative analysis demonstration, and in its cerebral tissue, IRF9 expression is about 4.3 times of normal structures.

[embodiment 2] mouse brain Infarction Model (I/R) obtains

1. laboratory animal grouping: male C57BL/6 strain wild-type mice, IRF9 knock out mice and head specificity IRF9 transgenic mice and non-transgenic mice, by Cell transplantation, set up Cerebral Infarction Model (I/R).Be divided at random 8 groups, every group of 10 mices: C57BL/6 strain wild-type mice sham operated rats (WT SHAM) and I/R art group (WT I/R), IRF9 knock out mice sham operated rats (KO SHAM) and I/R art group (KO I/R), non-transgenic mice sham operated rats (NTG SHAM) and I/R art group (NTG I/R), Neuron-specific IRF9 transgenic mice sham operated rats (TG SHAM) and I/R art group (TG I/R).

2. line bolt method cerebral infarction I/R operation adopts MCAO(middle cerebral artery occlusion, middle cerebral artery occlusion) model manipulation flow process:

(1) capture mice, use 3% isoflurane anesthesia mice, 8% sodium sulfide is sloughed the Mus hair of cervical region, and calvarium Mus hair is cut rapidly with operating scissors, 3% povidone iodine sterilization cervical region and calvarium skin 2 times, the de-iodine of 75% ethanol 1 time;

(2) at the calvarium position of mice cross sections, expose skull, with tweezers, peel off gently the connective tissue of skull surface.The fibre-optical probe of laser Doppler flowmetry is fixed on to bregma rear 2mm, the position of left side 5mm with biogum;

(3) mice is lain on the back fixing, neck median line otch, along sternocleidomastoid inner edge separating muscle and fascia, separates left carotid (CCA), external carotid artery (ECA) and internal carotid artery (ICA).At ECA distal end, with 8-0 toe-in, prick, ECA proximal part place hanging wire is standby.With arteriole, press from both sides temporary transient folder and close ICA, CCA; Then in the middle of the ligation of ECA distal end and proximal part hanging wire, cut an osculum, line bolt is sent to CCA by clip, and the hanging wire of ECA proximal part is made a call to a slip-knot at clip, elasticity can free in and out with line bolt but the sense that slightly rubs is advisable, loose ICA bulldog clamp again, line bolt is sent into ICA, from vascular bifurcation, start to calculate distance, when insertion depth, in about 9-11mm, stop to the decline power that is hampered of blood flow.At this moment will fasten gently and fasten line around ECA proximal part place slip-knot, whole process must maintain the anus temperature of mice at 37 ± 0.5 ℃;

(4) from line bolt, enter decline power stopping time that is hampered of cerebrovascular to blood flow and start timing, after 45min, first unclamp ECA proximal part place slip-knot, line bolt is extracted, and ECA proximal part place slip-knot is tightened, unclamp rapidly CCA place bulldog clamp, and by the ligation of ECA proximal part (Sham group from line bolt, enter cerebrovascular to blood flow decline take out Outlet bolt while being hampered power).Note observing restoration of blood flow situation, select blood flow to decline more than 75%, the mice that restoration of blood flow reaches more than 70% is included experiment in;

(5) sew up mice cervical region and skin of head, and with the povidone iodine wound of sterilizing.After operation finishes, mice is placed in incubator, case temperature maintains 28 ℃, and feedwater and feedstuff are to drawing materials.

[embodiment 3] Cerebral Infarction Model (I/R) mouse brain Infarction volume is measured

The evaluation index of the cerebral ischemia/reperfusion injury order of severity mainly comprises the scoring of infarction of brain volume and function of nervous system, these indexs all with ischemia/reperfusion injury order of severity positive correlation.

(1) 24h after operation respectively, 72h, carries out function of nervous system and behavioristics's scoring before 7d draws materials;

Based on Berderson function of nervous system scoring improve one's methods (9 points of systems):

0 point: the symptom that impassivity is impaired;

1 point: while carrying tail, offside forelimb is curled, or can not arrive Ipsilateral forelimb completely;

2 points: while carrying tail, in offside shoulder, receive;

3 points: horizontal sliding: while promoting to offside, resistance declines;

4 points: can be spontaneous to all directions motions, but only to offside, turn when de-tail;

5 points: during autonomic movement, turn-take or only to turning;

6 points: without autonomic movement, only motion when stimulating;

7 points: without autonomic movement, during stimulation also without motion;

8 points: the death relevant with cerebral ischemia.

(2) capture mice, lumbar injection 3% pentobarbital sodium anesthetized mice, cuts off mice thoracic cavity, breaks heart blood-letting;

(3) skin of neck after volume fraction 75% alcohol disinfecting, cut off rear skin of neck, expose head and cervical region, from cervical vertebra, cut off neck marrow, rear musculi colli is removed in separation, and eye scissors is longitudinally cut off the outer skull of brain stem cerebellum, with stricture of vagina tooth pincers strip off skull, separate brain surface's cerebral dura mater, avoid cerebral dura mater to scratch cerebral tissue.While getting brain, from oblongata, careful separation basis cranii tissue, avoids damaging brain;

(4) cerebral tissue taking off is put into the culture dish rinse that PBS is housed, blotted PBS with gauze, cerebral tissue is put into 1mm mouse brain mould, be placed in-20 ℃ of refrigerators frozen (being no more than 4h);

(5) cerebral tissue 2,3, 5-Triphenyltertrazoliumchloride (2,3,5-Triphenyltetrazolium chloricej, TTC) dyeing: from-20 ℃ of refrigerators, take out cerebral tissue, be cut into immediately 1mm slab, comprise that bregma front cuts 4, rear is cut 3, cuts altogether 7.Section is placed in immediately to the serum bottle of 10ml 2% TTC solution, 37 ℃ of constant-temperature incubation 10min.Frequently stir section, make even tissue dyeing.After normal cerebral tissue's dyeing, be cerise, and infarcted region is pale asphyxia;

(6) cerebral tissue is fixed: the cerebral tissue in beaker and solution are together proceeded in the cup of carrying out labelling, discard TTC solution, with the fixing brain tissue slice of 10% neutral formalin solution, take pictures and use IPP software analysis after 24h;

(7) cerebral infarction volume calculates: Infarction volume %=(not Infarction volume of offside cerebral hemisphere volume-infarction side)/(offside cerebral hemisphere volume × 2) × 100%;

Total Infarction volume is 7 brain sheet result data sums separately.

TTC is fat-soluble photaesthesia complex, it is the proton acceptor of pyridine-nucleoside structure enzyme system in respiratory chain, take on a red color, and in ischemic tissue, dehydrogenase activity declines with dehydrogenase reaction in normal structure, can not react, therefore can not change and be pale asphyxia.

TTC coloration result as shown in Figure 2, pours into IRF9-KO mice Infarction volume after 24 hours through I/R ischemia 45min again and reduces compared with wild-type mice; And this protective effect still continues at I/R for postoperative 72 hours, 7 days, and cerebral tissue infarction is all lower than wild-type mice, and function of nervous system's scoring all improves at I/R for postoperative 24 hours, 72 hours and 7 days.

As shown in Figure 3, through I/R ischemia 45min, pouring into IRF9-TG mice Infarction volume after 24 hours obviously increases the weight of compared with wild-type mice again; And this deterioration acts on I/R and still continues for postoperative 72 hours, and cerebral tissue infarction is than the equal height of wild-type mice.And function of nervous system's scoring all worsens at I/R for postoperative 24 hours and 72 hours.

[embodiment 4] cerebral tissue infarction surrounding zone neuronal cell apoptosis situation is measured

1. cerebral tissue frozen section preparation

1) experiment mice is pressed the anesthesia of 50mg/kg dosage lumbar injection pentobarbital sodium;

2) open breast and expose heart, puncture as left ventricle with injection needle, cut off right atrium simultaneously;

3) with 0.1mol/L μ PBS(pH7.4) after 100mmHg pressure perfusion loses color to liver, with 4% paraformaldehyde perfusion 15min;

4) open cranium and take out rapidly mouse brain, after room temperature 4% paraformaldehyde, fix 6-8h;

5) olfactory bulb and the cerebellum of excision cerebral tissue, then prolong median line brain is divided into first latter two part, fixes 15min again with previous fixative;

6) be immersed in subsequently containing in the phosphate buffer of 30% sucrose, 4 ℃ of refrigerators sink to the bottom and spend the night;

7) after 30% sucrose mixes by 1:1 with OCT, in right amount in embedding frame, the tissue of back is taken out, suck liquid on gauze after, in this embedding frame, soak a little while, be transferred to again and first added in another embedding frame of 2 OCT, the position of adjusting tissue, makes it just in time be positioned at the center of embedding frame;

8) will contain the embedding frame of tissue, and move in dry ice, and make it in horizontal position as far as possible, and slightly, after a little while, continue to add OCT, certain height is organized in submergence, after OCT solidifies, is stored in the refrigerator of-80 ℃;

9) by the standardization program of freezing microtome, cut the frozen section of 5 μ m standby.

2.TUNEL test kit staining examine apoptosis.

With TUNEL test kit staining examine apoptosis.(TUNEL test kit: ApopTag Plus In Situ Apoptosis Fluorescein Detection Kit (S7111, Chemicon)):

1) ice is cut to tissue slice and is placed in the paraformaldehyde of (pH 7.4) 1%, the fixing hydrolysis of room temperature 10 minutes;

2) PBS washes twice, each 5 min;

3) be placed in the ethanol of pre-cooling: acetic acid (2:1) solution ,-20 ℃ are soaked 5 minutes, remove unnecessary liquid, but note dry;

4) PBS washes twice, each 5 min;

5) filter paper carefully sucks unnecessary liquid, presses immediately 75 μ L/5 cm in section ²directly add level pad, incubated at room 1-5 min;

6) filter paper carefully sucks unnecessary liquid, presses immediately 55 μ L/5 cm in section ²directly add TdT enzyme reaction solution, be placed in lucifuge moisture preservation box effect 1 h(negative control and add the not reactant liquor containing TdT enzyme);

7) section is placed in to termination/lavation buffer solution, shakes gently 15 sec, incubated at room 10 min; Now prepare appropriate anti digoxin antibody, be preheated to room temperature, note lucifuge;

8) PBS washes three times, each 1 min;

9) filter paper carefully sucks unnecessary liquid, directly in section, presses 65 μ L/5 cm ²add anti digoxin antibody, under room temperature, in the wet box of lucifuge insulation, act on 1 h;

10) PBS washes four times, each 2 min;

11) SlowFade Gold antifade reagent with DAPI(Invitrogen, S36939) mounting;

12) at fluorescence microscopy Microscopic observation counting Apoptotic neuron cell.

3. FJB(Fluoro Jade B) dyeing

1) ice is cut to tissue slice dries 1 hour in baking oven;

2) 1% NaOH+80% dehydrated alcohol 5min;

3) 70% dehydrated alcohol 2min;

4）dd H2O 2min；

5) Flouro Jade B diluent (AG310, Millipore, Billerica, MA), room temperature, lucifuge 20min;

6）dd H2O 1min X3；

7) in baking oven, dry sheet 5-10min;

8) dimethylbenzene > 1min;

9) mounting, takes pictures.

As shown in Figure 4, we have detected IRF9-KO mice and postoperative 24 hours cerebral tissue infarction surrounding zone neuronal cell apoptosis situations of wild-type mice I/R to cerebral tissue infarction surrounding zone neuronal cell apoptosis situation measurement result.Fluoro Jade B and TUNEL apoptosis detection display, the apoptotic cell quantity of IRF9-KO group mice is obviously few than WT group mice, and the apoptotic cell quantity of IRF9-TG group mice is obviously many than NTG group mice.It is dead relevant when further prompting IRF9 is to neuronal cell ischemia/reperfusion.These results show, suppress IRF9 expression and can improve cerebral tissue ischemia/reperfusion injury, and may be closely related with neuronal cell apoptosis.

Our achievement in research shows, in the damage that IRF9 KO mice causes at Cell transplantation, after we find that IRF9 knocks out, mice Infarction volume significantly reduces, and function of nervous system obviously improves, and neuronal apoptosis also obviously reduces.Prove that IRF9 gene has important deterioration effect in apoplexy disease model.

Above-described embodiment is preferably embodiment of the present invention; but embodiments of the present invention are not restricted to the described embodiments; other any do not deviate from change, the modification done under spirit of the present invention and principle, substitutes, combination, simplify; all should be equivalent substitute mode, within being included in protection scope of the present invention.

SEQUENCE LISTING

<110> Wuhan University

<120> interferon regulatory factor 9(IRF9) and the application of inhibitor in apoplexy disease

<130> 1

<160> 4

<170> PatentIn version 3.3

<210> 1

<211> 35

<212> DNA

<213> Artificial

<223> IRF9 forward primer

<400> 1

ccagattacg ctgatatggc atcaggcagg gcacg 35

<210> 2

<211> 35

<212> DNA

<213> Artificial

<223> IRF9 downstream primer

<400> 2

agggaagatc ttgattcagc aggctctaca caggg 35

<210> 3

<211> 35

<212> DNA

<213> Artificial

<223> detects forward primer

<400> 3

ccagattacg ctgattgtga ccggaacggc gggcg 35

<210> 4

<211> 35

<212> DNA

<213> Artificial

<223> detects reverse primer

<400> 4

agggaagatc ttgatttaga cggtgatctg ttgat 35

Claims (4)

1. IRF9 application in screening treatment apoplexy disease medicament as drug targets.

2. the application of the inhibitor of an IRF9 in preparation treatment apoplexy disease medicament.

3. a medicine for the treatment of apoplexy disease, is characterized in that: comprise IRF9.

4. application according to claim 2 or medicine claimed in claim 3, is characterized in that: the inhibitor of described IRF9 is the one in siRNA, the rna interference vector of IRF9 gene or the antibody of IRF9 of IRF9 gene.

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