Application of GSK8612 in treatment of autoimmune and inflammatory diseases

Abstract

The invention relates to application of GSK8612 in treatment of autoimmune and inflammatory diseases. The invention mainly investigates the safety and effectiveness of the GSK8612 in the treatment of the autoimmune and inflammatory diseases, provides the application of the GSK8612 in the treatment of the autoimmune and inflammatory diseases, and proves that the GSK8612 can play a role in inhibiting the excessive activation of macrophages through in-vivo and in-vitro pharmacological experiments; the compound has a remarkable treatment effect on acute peritonitis and systemic inflammatory response of mice, and can be further used for preparing immunosuppressive drugs.

Description

Technical Field

[0001] The present invention belongs to the field of medical technology and relates to the application of GSK8612 in the treatment of autoimmune and inflammatory diseases. Background Art

[0002] Inflammatory diseases are a large group of diseases characterized by abnormal activation of the immune system. They can be divided into acute inflammation (such as infectious pneumonia) and chronic inflammation (such as rheumatoid arthritis) according to the course of the disease. About 5% of the world's population suffers from chronic inflammatory diseases, and their pathogenesis involves the dysregulation of the complex regulatory network of innate immunity and adaptive immunity. When there is an imbalance between pro-inflammatory factors (TNF-α, IL-6, etc.) and anti-inflammatory factors, it may cause persistent tissue damage. Typical pathological characteristics include inflammatory cell infiltration, changes in vascular permeability, and fibrosis formation.

[0003] Representative diseases of systemic inflammatory disease, such as systemic lupus erythematosus (SLE), have a core mechanism of immune tolerance breakdown leading to multi-organ involvement. A variety of autoantibodies can be detected in patients, and typical symptoms include butterfly rash, joint swelling and pain, and kidney damage. The current treatment of systemic inflammatory reactions mainly adopts a step-by-step comprehensive strategy. The traditional regimen is based on glucocorticoids, combined with immunosuppressants (such as methotrexate and cyclophosphamide) to control excessive immune activation. The use of biological agents (anti-TNF-α, IL-6 receptor monoclonal antibodies, etc.) has increased the remission rate of moderate to severe patients to 50% to 70%. However, the clinic still faces three major challenges: about 30% of patients develop hormone resistance, long-term immunosuppression leads to an increased risk of opportunistic infections (incidence of about 18%), and complications such as metabolic syndrome. Therefore, the search for new, safe, efficient, and precisely targeted immunosuppressants remains a major challenge and of great significance.

[0004] Macrophages and neutrophils are core effector cells of the inflammatory response. Neutrophils, acting as a "rapid response force" in acute inflammation, are recruited to sites of injury via chemokines (such as IL-8) and directly eliminate pathogens through phagocytosis, degranulation (release of myeloperoxidase and elastase), and NETs (neutrophil extracellular traps). Their burst of reactive oxygen species (ROS) can create a bactericidal microenvironment, but excessive release can cause tissue damage. Macrophages have a dual regulatory function: in the early stages of inflammation, they recognize danger signals through pattern recognition receptors (TLRs, etc.) and secrete proinflammatory cytokines such as TNF-α and IL-1β to amplify inflammation. Later, they switch to an anti-inflammatory phenotype (M2 type), secreting IL-10 and clearing apoptotic neutrophils to promote tissue repair. Both macrophages form a positive feedback loop through the CXCL8 / CXCR2 axis. IL-23 produced by macrophages can also activate neutrophils to release proinflammatory mediators. In chronic inflammation, persistently activated macrophages induce fibrosis through TGF-β, while the degree of neutrophil infiltration is positively correlated with disease activity and becomes a therapeutic target (such as anti-IL-17 inhibition of neutrophil recruitment).

[0005] GSK8612, a novel TBK1 (TANK-binding kinase 1) inhibitor, is opening up a new avenue for the treatment of inflammation. TBK1 is a key node in the innate immune signaling pathway, regulating type I interferon production by phosphorylating IRF3 and participating in NF-κB activation. Previous studies have shown that GSK8612 may alleviate cisplatin-induced acute kidney injury in mice by inhibiting endoplasmic reticulum stress, apoptosis, and macrophage inflammatory responses. The compound has now completed a Phase I clinical trial (NCT04630769), with a single dose of 800 mg well tolerated in healthy subjects. The main metabolic pathway is CYP3A4-mediated oxidation. In this study, we focused on the immunomodulatory effects of GSK8612 and found that the compound has significant inhibitory effects on both innate immunity (macrophages / neutrophils) and adaptive immunity (T / B cells), and has great potential for development as an anti-inflammatory targeted drug. Summary of the Invention

[0006] In response to the above problems, the present invention proposes the use of GSK8612 in the treatment of autoimmune and inflammatory diseases, which effectively solves the problems in the prior art.

[0007] In order to achieve the above object, the technical solution adopted by the present invention is as follows:

[0008] The application of GSK8612 in the treatment of autoimmune and inflammatory diseases.

[0009] Preferably, the dosage of GSK8612 is 0.1 to 20 mg per kilogram.

[0010] Preferably, the administration route of GSK8612 is one or more combinations of oral, intravenous, intramuscular, nasal, oral mucosa, skin or rectal.

[0011] Preferably, the dosage of GSK8612 can be administered 1-4 times a day.

[0012] Compared with the prior art, the present invention has the following beneficial effects:

[0013] The present invention mainly investigates the safety and effectiveness of GSK8612 in the treatment of autoimmune and inflammatory diseases, provides the application of GSK8612 in the treatment of autoimmune and inflammatory diseases, and proves through in vitro and in vivo pharmacological experiments that GSK8612 can inhibit the excessive activation of macrophages, and has a significant therapeutic effect on acute peritonitis and systemic inflammatory response in mice, and can be used to prepare immunosuppressive drugs. The present invention focuses on the functional effects of compound GSK8612 on immune cells (including innate immune cells and adaptive immune cells), and the molecular mechanisms of action are different. The compound GSK8612 involved in the present invention inhibits the release of neutrophil reactive oxygen species and the expression of macrophage inflammatory factors by inhibiting the STAT1-AKT signaling pathway, and regulates the activation of adaptive immune cells (T / B cells). It is revealed that the compound GSK8612 involved inhibits the inflammatory response by regulating the STAT1-AKT axis. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] Figure 1 To determine the inhibitory effect of GSK8612 on LPS-induced neutrophil release of reactive oxygen species.

[0015] Figure 2 To determine the inhibitory effect of GSK8612 on LPS-induced neutrophil activation.

[0016] Figure 3 To determine the inhibitory effect of GSK8612 on the expression of LPS-induced macrophage inflammatory factors TNF-α, IL-6, MCP-1, MIP-1α, IP-10 and CCL-5.

[0017] Figure 4 To determine the inhibitory effect of GSK8612 on LPS-induced macrophage inflammatory factors TNF-α, IL-6, MCP-1, MIP-1α and IP-10 secretion.

[0018] Figure 5 To determine the inhibitory effect of GSK8612 on LPS-induced macrophage activation signaling pathway.

[0019] Figure 6This study was to determine the inhibitory effect of GSK8612 on thioglycollate-induced peritonitis in mice.

[0020] Figure 7 To determine the inhibitory effect of GSK8612 on adaptive immune cell activation caused by systemic inflammatory response.

[0021] Figure 8 This is a comparative determination of the inhibitory effects of GSK8612 and DEX on the expression of LPS-induced macrophage inflammatory factors TNF-α, IL-6, MCP-1 and IP-10. DETAILED DESCRIPTION

[0022] The following will clearly and completely describe the technical solutions in the embodiments of the present invention in conjunction with the accompanying drawings. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative efforts are within the scope of protection of the present invention.

[0023] The following is combined with Figures 1 to 8 The specific embodiments of the present invention are described in further detail.

[0024] Example 1, by Figure 1 As shown, this example is used to determine the inhibitory effect of GSK8612 on the release of reactive oxygen species by neutrophils induced by LPS:

[0025] BALB / c mice were sacrificed by cervical dislocation, soaked in 75% alcohol for 5 minutes, and placed in a sterile culture dish. The skin of the mouse hind legs was cut open, and the bilateral femurs were carefully removed. The mouse bone marrow cells were flushed out of the centrifuge tube using a 1ml syringe with phosphate-buffered saline (PBS), and the tube was centrifuged at 300g for 5 minutes at room temperature. The supernatant was removed, and 5ml of red blood cell lysis medium was added to resuspend the cells. The red blood cells were lysed at room temperature for 2 minutes. Then, 5ml of IMDM medium containing 2% fetal bovine serum was added to terminate the lysis. The tube was centrifuged at 300g for 5 minutes at room temperature, and the supernatant was removed. 5ml of IMDM medium containing 2% fetal bovine serum was added to wash once, and finally, IMDM medium containing 2% fetal bovine serum, 100U / ml ampicillin, and 100μg / ml streptomycin was added to resuspend the cells and adjust the cell concentration to 5×10 6 pcs / ml.

[0026] Dihydrorhodamine 123 (DHR123) was added to the above cells to a final concentration of 1 μM. After incubation for 15 minutes, different concentrations of GSK8612 (final concentrations of 5, 10, and 20 μM) were added. LPS (final concentration of 1 μg / ml) was then added. After incubation for 1.5 hours, the cells were collected. Centrifuged at 4°C and 300g for 5 minutes, the supernatant was discarded, and 200 μl of flow cytometry staining buffer was added to resuspend the cells. Dead cell stain 7-AAD and APC-labeled rat anti-mouse Ly6G antibody were then added. The cells were kept in a dark ice bath for 30 minutes, washed twice with flow cytometry staining buffer (PBS containing 0.2% BSA), and 7-AAD was detected by flow cytometry. - Ly6G + The fluorescence intensity of the FITC channel of neutrophils (the fluorescence channel of the products after the reaction of DHR123 and reactive oxygen species) was used to detect the amount of reactive oxygen species produced. Each experiment was repeated 3 times, and the data are expressed as mean ± standard deviation.

[0027] The results showed that LPS stimulation of neutrophils significantly enhanced the release of reactive oxygen species compared with the blank group (#P<0.05vsControl), and GSK8612 treatment significantly inhibited the release of superoxide from neutrophils (*P<0.05vsLPS).

[0028] Therefore, the example demonstrates that compound GSK8612 has a significant inhibitory effect on lipopolysaccharide (LPS)-induced neutrophil activation and superoxide release.

[0029] Example 2, by Figure 2 As shown, this example is used to determine the inhibitory effect of GSK8612 on LPS-induced neutrophil activation:

[0030] Mouse bone marrow cells were prepared according to the method described in Example 1, and different concentrations of GSK8612 (final concentration 5, 10, 20 μM) were added. LPS (final concentration 1 μg / ml) was then added, and after incubation for 1.5 hours, the cells were collected. Centrifuge at 4°C and 300g for 5 minutes, discard the supernatant, add 200 μl flow cytometry staining buffer to resuspend the cells, and then add dead cell stain 7-AAD, APC-labeled rat anti-mouse Ly6G antibody, PE-labeled rat anti-mouse CD11b antibody, PE-CY7-labeled rat anti-mouse CD62L antibody, protect from light and ice bath for 30 minutes, wash twice with flow cytometry staining buffer (PBS containing 0.2% BSA), and detect 7-AAD-Ly6G by flow cytometry. + Upregulation of CD11b and downregulation of CD62L on the surface of neutrophils. Each experiment was repeated three times, and the data are expressed as mean ± standard deviation.

[0031] Figure 2Middle: (A) GSK8612 can inhibit LPS-induced upregulation of CD11b, an activation marker on the surface of neutrophils; (B) GSK8612 can inhibit LPS-induced downregulation of CD62L, an adhesion molecule on the surface of neutrophils.

[0032] The results showed that after LPS stimulation of neutrophils, it could significantly induce neutrophils to downregulate CD62L and upregulate CD11b compared with the relative solvent control group (#P<0.05vsControl), and GSK8612 could significantly inhibit the upregulation of CD11b and the downregulation of CD62L (*P<0.05vsLPS).

[0033] Therefore, this example demonstrates that the compound GSK8612 according to the present invention has a significant inhibitory effect on LPS-induced macrophage activation through real-time quantitative polymerase chain reaction and enzyme-linked immunosorbent assay.

[0034] Example 3, by Figure 3 As shown, this example is used to determine the inhibitory effect of GSK8612 on LPS-induced macrophage inflammatory factor expression:

[0035] Mouse bone marrow cells were prepared according to the method described in Example 1, and the cells were adjusted to 3×10 6 Cells were seeded into 12-well plates with a total volume of 1 ml of culture medium and cultured in a cell culture incubator at 37°C and 5% CO2 for 2 h. The culture medium was then aspirated and fresh culture medium was added for washing once. Finally, 1 ml of culture medium and cytokine M-CSF (final concentration 20 ng / ml) were added. On the third day, 0.5 ml of fresh culture medium and M-CSF were added to each well. On the sixth day, adherent cells were collected and centrifuged at 300 g for 5 min at room temperature. The supernatant was discarded and the cells were resuspended in DMEM containing 10% fetal bovine serum to adjust the cell concentration to 1.5 × 10 6 Cells were collected at 47°C for 24 h. Different concentrations of GSK8612 were added (final concentrations of 5, 10, and 20 μM). LPS was then added (final concentration of 1 μg / ml). After incubation for 6 h, the cells were collected. 1 ml of Trizol was added to lyse the cells, and total mRNA was extracted using an mRNA extraction kit. Reverse transcription was then used to synthesize cDNA, and finally, real-time fluorescence quantitative polymerase chain reaction (RT-PCR) was performed using a variety of cytokine primers. The expression levels of various gene mRNAs relative to GAPDH were calculated. Each experiment was repeated 3 times, and the data are presented as mean ± standard deviation.

[0036] RT-qPCR results showed that after LPS stimulation of macrophages, the expression levels of inflammatory factors TNF-α, IL-6 and chemokines MCP-1, MIP-1α, IP-10, and CCL-5 were significantly increased (#P<0.05vsControl). GSK8612 could significantly inhibit the expression of the above cytokines (*P<0.05vsLPS), especially the inhibition of IP-10 and MCP-1 was more significant and dose-dependent.

[0037] Example 4, by Figure 4 As shown, this example is used to determine the inhibitory effect of GSK8612 on LPS-induced macrophage inflammatory factor secretion:

[0038] Primary mouse macrophages were prepared according to the method in Example 3, and the cell concentration was adjusted to 1.5×10 6 Macrophages were seeded at 40 μg / ml in 96-well plates. After the cells adhered and grew, different concentrations of GSK8612 (final concentrations of 5, 10, and 20 μM) were added. LPS (final concentration of 1 μg / ml) was then added. After incubation for 12 hours, the supernatant from each well was collected. Enzyme-linked immunosorbent assay (ELISA) was used to quantify the concentration of cytokines secreted by macrophages. Each experiment was repeated three times, and data are presented as mean ± standard deviation.

[0039] ELISA results showed that after LPS stimulation of macrophages, the secretion of inflammatory factors TNF-α, IL-6 and chemokines MCP-1, MIP-1α, and IP-10 increased significantly (#P<0.05vsControl). GSK8612 could significantly inhibit the expression of the above cytokines (*P<0.05vsLPS), especially the inhibition of IP-10 and MCP-1 was more significant, which was consistent with the results at the transcriptional level.

[0040] Example 5, by Figure 5 As shown, this example is used to determine the inhibitory effect of GSK8612 on the LPS-induced macrophage activation signaling pathway:

[0041] Primary mouse macrophages were prepared according to the method in Example 3, and the cell concentration was adjusted to 1.5×10 6 Cells were seeded into 6-well plates at 4% RI / ml. After the cells adhered and grew, different concentrations of GSK8612 (final concentrations of 5, 10, and 20 μM) were added. LPS (final concentration of 1 μg / ml) was then added, and after a 3-h incubation, cells were harvested from each well. Total cellular protein was extracted using RIPA lysis buffer, and changes in the phosphorylation levels of AKT, STAT1, P38, and P65 were detected by Western blot. Each experiment was repeated three times, and data are presented as mean ± standard deviation.

[0042] Figure 5Middle: (A) Western Blot analysis of the effect of GSK8612 on the protein expression levels of p-AKT (T308), p-STAT1, p-P38, and p-P65 in activated macrophages; (B) Quantity One software was used to perform grayscale analysis of protein bands.

[0043] The results showed that compared with the blank control group cells, GSK8612 alone did not cause changes in protein levels. However, LPS stimulation of macrophages significantly increased the levels of various phosphorylated proteins (#P<0.05vsControl). After LPS stimulation, the addition of different concentrations of GSK8612 significantly inhibited the protein expression of p-AKT (T308) and p-STAT1 (*P<0.05vsLPS), indicating that GSK8612 may inhibit the occurrence of inflammatory responses by inhibiting the activation of the STAT1-AKT signaling pathway. However, GSK8612 had no significant effect on the protein expression of p-P38 and p-P65, indicating that GSK8612 has no effect on the MAPK and NF-κB signaling pathways.

[0044] Therefore, this example demonstrates, through Western blotting experiments, that the compound GSK8612 of the present invention has a significant inhibitory effect on LPS-induced activation of the STAT1-AKT signaling pathway in macrophages.

[0045] Example 6, by Figure 6 As shown, this example is used to determine the inhibitory effect of GSK8612 on thioglycollate-induced mouse peritonitis:

[0046] Forty male Balb / c mice were randomly divided into a vehicle control group (Vehicle), a model group (Model), and low-, medium-, and high-dose GSK8612 groups (5, 10, and 20 μM). One hour after oral administration of the corresponding drug or vehicle (sodium carboxymethylcellulose), the model and treatment groups were intraperitoneally injected with 2 ml of Thioglycollate. Four hours after intraperitoneal injection, the peritoneal cells of the mice were washed with 5 ml of PBS, and the number of macrophages (F4 / 80 + CD11b + ) and neutrophil ratio (Ly6G + CD11b + ); in addition, the ELISA method was used to detect the levels of inflammatory factors TNF-α and IL-6 in the peritoneal lavage fluid.

[0047] Figure 6Middle: (AB) Flow cytometry was used to detect the changes in the ratio of macrophages and neutrophils in peritoneal cavity cells after GSK8612 treatment; (CD) ELISA was used to detect the levels of TNF-α and IL-6 in peritoneal lavage fluid.

[0048] The experimental results showed that thioglycollate could induce a strong inflammatory response in mice, including intraperitoneal Ly6G + CD11b + Increased neutrophil ratio and F4 / 80 + CD11b + The proportion of macrophages decreased, and the levels of inflammatory factors TNF-α and IL-6 in the peritoneal lavage fluid increased (#P<0.05vsVehicle). After treatment with GSK8612, the increase in neutrophils and the decrease in macrophages in the peritoneal cavity of mice caused by thioglycollate were effectively reversed. The proportion of neutrophils in the high-dose group of GSK8612 decreased by about 45%, which can effectively slow down the inflammatory response. At the same time, the levels of TNF-α and IL-6 in the peritoneal lavage fluid were also significantly reduced (*P<0.05vsModel), indicating that GSK8612 can effectively reduce the production of cytokine inflammatory storms.

[0049] Therefore, this example demonstrates, through in vivo animal experiments, that the compound GSK8612 according to the present invention has an inhibitory effect on thioglycollate-induced peritonitis in mice.

[0050] Example 7, by Figure 7 As shown, this example is used to determine the inhibitory effect of GSK8612 on adaptive immune cell activation caused by systemic inflammatory response:

[0051] Since LPS is administered intravenously to mice to establish a systemic inflammatory response model, it activates CD4 through the secretion of IL-15 by innate immune cells. + T cells, CD8 + T cells and B cells, so this experiment used this acute model to study the inhibitory effect of GSK8612 on the adaptive immune response in vivo. 40 male Balb / c mice were randomly divided into a vehicle control group (Vehicle), a model group (Model), and GSK8612 low, medium, and high dose groups (5, 10, and 20 μM). After 1 hour of oral administration of the corresponding drug or vehicle (sodium carboxymethyl cellulose) to each group, the model and treatment groups were intravenously injected with LPS (2 mg / kg). 24 hours after intravenous injection, spleen cells were obtained from the mice and CD4 + T cells, CD8 + T cells and B cells showed CD69 and CD86 expression.

[0052] Figure 7 Middle: (A) Flow cytometry was used to detect the CD4 + Expression of CD69 on the surface of T cells; (B) CD8 + (C) Expression of CD69 on the surface of B cells in the spleen of each group of mice; (D) Expression of CD86 on the surface of B cells in the spleen of each group of mice.

[0053] Flow cytometry results showed that GSK8612 could significantly inhibit LPS-induced CD4 + T cells, CD8 + The expression of CD69 on the surface of T cells and B cells, and the expression of CD86 on the surface of B cells (*P<0.05 vs Model), indicate that GSK8612 has a significant improvement effect on the systemic inflammatory response induced by LPS.

[0054] Therefore, this example demonstrates, through in vivo animal experiments, that the compound GSK8612 according to the present invention has an inhibitory effect on the activation of adaptive immune cells caused by the systemic inflammatory response induced by LPS.

[0055] Comparative Example 1, such as Figure 8 As shown:

[0056] In order to emphasize the anti-inflammatory effect of GSK8612, primary mouse macrophages were treated with it and dexamethasone (DEX) at the same time to compare the anti-inflammatory effects of the two. Macrophages were prepared according to the method in Example 3, and a blank control group (Control), an LPS (1 μg / ml) group, an LPS+GSK8612 (5 μM) group, and an LPS+DEX (5 μM) group were set up. After incubation for 6 hours, cells from each group were collected, and the gene expression levels of TNF-α, IL-6, MCP-1, and IP-10 were detected by RT-qPCR. Each experiment was repeated 3 times, and the data are expressed as mean ± standard deviation.

[0057] The results showed that dexamethasone could significantly inhibit the expression of LPS-induced inflammatory factors such as TNF-α, IL-6, MCP-1 and IP-10 in macrophages (#P<0.05vsLPS). The inhibitory effect of GSK8612 on TNF-α and MCP-1 was not significantly different from that of dexamethasone. However, it is worth noting that the inhibitory effect of GSK8612 on IL-6 and IP-10 was more significant than that of dexamethasone (*P<0.05vsDEX).

[0058] It should be further explained that the compound GSK8612 of the present invention can be administered orally, intravenously, intramuscularly, nasally, through the oral mucosa, through the skin or through the rectum.

[0059] The dosage of the compound GSK8612 of the present invention is 0.1 to 20 mg per kilogram of body weight.

[0060] It should be further noted that the compound GSK8612 of the present invention can be administered in liquid or solid dosage forms. For example, liquid dosage forms can be true solutions, colloids, microparticles, emulsions, or suspensions. Other dosage forms include tablets, capsules, pellets, aerosols, pills, powders, solutions, suspensions, emulsions, granules, suppositories, and lyophilized powder injections.

[0061] It should be further explained that, in the specific implementation process, the inflammation or inflammation-related diseases to which the present invention is applicable include sepsis, rheumatoid arthritis, osteoarthritis, gastrointestinal inflammation, polymyositis, neuroinflammation, chemical pain, inflammatory pain, skin inflammation, retroperitoneal fibrosis, hepatitis, pneumonia, pancreatitis, allergic inflammation, and systemic inflammatory response syndrome.

[0062] The present invention mainly investigates the safety and effectiveness of GSK8612 in the treatment of autoimmune and inflammatory diseases, provides the application of GSK8612 in the treatment of autoimmune and inflammatory diseases, and proves through in vitro and in vivo pharmacological experiments that GSK8612 can inhibit the excessive activation of macrophages, and has a significant therapeutic effect on acute peritonitis and systemic inflammatory response in mice, and can be used to prepare immunosuppressive drugs. The present invention focuses on the functional effects of compound GSK8612 on immune cells (including innate immune cells and adaptive immune cells), and the molecular mechanisms of action are different. The compound GSK8612 involved in the present invention inhibits the release of neutrophil reactive oxygen species and the expression of macrophage inflammatory factors by inhibiting the STAT1-AKT signaling pathway, and regulates the activation of adaptive immune cells (T / B cells). It is revealed that the compound GSK8612 involved inhibits the inflammatory response by regulating the STAT1-AKT axis.

[0063] Although the present invention has been described in detail with reference to the aforementioned embodiments, it is still possible for those skilled in the art to modify the technical solutions described in the aforementioned embodiments, or to make equivalent substitutions for some of the technical features therein. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. Application of GSK8612 in the treatment of autoimmune and inflammatory diseases.

2. The use of GSK8612 in the treatment of autoimmune and inflammatory diseases according to claim 1, characterized in that: The dosage of GSK8612 is 0.1 to 20 mg per kilogram.

3. The use of GSK8612 in the treatment of autoimmune and inflammatory diseases according to claim 1 or 2, characterized in that: The administration route of GSK8612 is one or more combinations of oral administration, intravenous injection, intramuscular injection, nasal cavity, oral mucosa, skin or rectum.

4. The use of GSK8612 in the treatment of autoimmune and inflammatory diseases according to claim 2, characterized in that: The dosage of GSK8612 can be administered 1-4 times a day.

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