Research progress on the role of interleukin-1 in immune response and metabolic reprogramming of macrophages against Mycobacterium tuberculosis

doi:10.19983/j.issn.2096-8493.20230108

Abstract

Abstract:

Tuberculosis caused by Mycobacterium tuberculosis (MTB), remains an important chronic inflammatory respiratory infectious disease. The pathogenesis of MTB depends on its ability to regulate the host metabolism. The host macrophage metabolic plasticity plays a key role in the progress of tuberculosis. The host release of IL-1 during MTB infection is critical for host defence and is subject to the host metabolic status. We reviewed the secretion of IL-1 during MTB infection and its effect on host resistance, the regulation of IL-1 by host macrophage metabolic reprogramming, and the crosstalk between IL-1 and other cytokines. This can deepen our understanding of host resistance to infection and the role of IL-1.

Key words: Mycobacterium tuberculosis, Interleukin-1, Macrophage, Metabolic reprogramming

CLC Number:

R52
R392

Yan Yaru, Xie Jianping. Research progress on the role of interleukin-1 in immune response and metabolic reprogramming of macrophages against Mycobacterium tuberculosis[J]. Journal of Tuberculosis and Lung Disease , 2023, 4(6): 511-518. doi: 10.19983/j.issn.2096-8493.20230108

Figures/Tables 3

References 81

[1]	World Health Organization. Global tuberculosis report 2022. Geneva: World Health Organization, 2022.
[2]	Ernst JD. The immunological life cycle of tuberculosis. Nat Rev Immunol, 2012, 12(8):581-591. doi:10.1038/nri3259. pmid: 22790178
[3]	Cohen SB, Gern BH, Delahaye JL, et al. Alveolar macrophages provide an early Mycobacterium tuberculosis niche and initiate dissemination. Cell Host Microbe, 2018, 24(3):439-446. doi:10.1016/j.chom.2018.08.001. pmid: 30146391
[4]	Wynn TA, Chawla A, Pollard JW. Macrophage biology in development, homeostasis and disease. Nature, 2013, 496(7446):445-455. doi:10.1038/nature12034.
[5]	Haldar M, Murphy KM. Origin, development, and homeostasis of tissue-resident macrophages. Immunol Rev, 2014, 262(1):25-35. doi:10.1111/imr.12215. pmid: 25319325
[6]	Murray PJ, Allen JE, Biswas SK, et al. Macrophage Activation and Polarization: Nomenclature and Experimental Guidelines. Immunity, 2014, 41(1):14-20. doi:10.1016/j.immuni.2014.06.008. pmid: 25035950
[7]	Martinez FO, Sica A, Mantovani A, et al. Macrophage activation and polarization. Front Biosci, 2008, 13:453-461. doi:10.2741/2692.
[8]	Xue J, Schmidt SV, Sander J, et al. Transcriptome-Based Network Analysis Reveals a Spectrum Model of Human Macrophage Activation. Immunity, 2014, 40(2):274-288. doi:10.1016/j.immuni.2014.01.006. pmid: 24530056
[9]	Shi LB, Jiang QK, Bushkin Y, et al. Biphasic Dynamics of Macrophage Immunometabolism during Mycobacterium tuberculosis Infection. Mbio, 2019, 10(2):e02550-18. doi:10.1128/mBio.02550-18.
[10]	O’neill LA, Pearce EJ. Immunometabolism governs dendritic cell and macrophage function. J Exp Med, 2016, 213(1):15-23. doi:10.1084/jem.20151570.
[11]	Lachmandas E, Rios-Miguel AB, Koeken V, et al. Tissue Metabolic Changes Drive Cytokine Responses to Mycobacterium tuberculosis. J Infect Dis, 2018, 218(1):165-170. doi:10.1093/infdis/jiy173. pmid: 29618104
[12]	Netea MG, van de Veerdonk FL, van der Meer JWM, et al. Inflammasome-Independent Regulation of IL-1-Family Cytokines. Annu Rev Immunol, 2015, 33:49-77. doi:10.1146/annurev-immunol-032414-112306. pmid: 25493334
[13]	Yuan XL, Peng X, Li Y, et al. Role of IL-38 and Its Related Cytokines in Inflammation. Mediators Inflamm, 2015, 2015:807976. doi:10.1155/2015/807976.
[14]	Palomo J, Dietrich D, Martin P, et al. The interleukin (IL)-1 cytokine family-Balance between agonists and antagonists in inflammatory diseases. Cytokine, 2015, 76(1):25-37. doi:10.1016/j.cyto.2015.06.017.
[15]	Zhu Q, Kanneganti TD. Cutting Edge: Distinct Regulatory Mechanisms Control Proinflammatory Cytokines IL-18 and IL-1β. J Immunol, 2017, 198(11):4210-4215. doi:10.4049/jimmunol.1700352. pmid: 28468974
[16]	Gracie JA, Robertson SE, Mcinnes IB. Interleukin-18. J Leukoc Biol, 2003, 73(2):213-224. doi:10.1189/jlb.0602313.
[17]	Cayrol C, Girard JP. The IL-1-like cytokine IL-33 is inactivated after maturation by caspase-1. Proc Natl Acad Sci U S A., 2009, 106(22):9021-9026. doi:10.1073/pnas.0812690106.
[18]	Gresnigt MS, Van De Veerdonk FL. Biology of IL-36 cytokines and their role in disease. Semin Immunol, 2013, 25(6):458-465. doi:10.1016/j.smim.2013.11.003. pmid: 24355486
[19]	Conti P, Carinci F, Lessiani G, et al. Potential therapeutic use of IL-37: a key suppressor of innate immunity and allergic immune responses mediated by mast cells. Immunol Res, 2017, 65(5):982-986. doi:10.1007/s12026-017-8938-7. pmid: 28748328
[20]	Silverio D, Goncalves R, Appelberg R, et al. Advances on the Role and Applications of Interleukin-1 in Tuberculosis. Mbio, 2021, 12(6):e0313421. doi:10.1128/mBio.03134-21.
[21]	Cooper AM, Mayer-Barber KD, Sher A. Role of innate cytokines in mycobacterial infection. Mucosal Immunol, 2011, 4(3):252-260. doi:10.1038/mi.2011.13. pmid: 21430655
[22]	Ravesloot-Chávez MM, Dis EV, Stanley SA. The Innate Immune Response to Mycobacterium tuberculosis Infection. Annu Rev Immunol, 2021, 39:611-637. doi:10.1146/annurev-immunol-093019-010426. pmid: 33637017
[23]	Mayer-Barber KD, Barber DL, Shenderov K, et al. Caspase-1 independent IL-1β production is critical for host resistance to mycobacterium tuberculosis and does not require TLR signaling in vivo. J Immunol, 2010, 184(7):3326-30. doi:10.4049/jimmunol.0904189. pmid: 20200276
[24]	Abdalla H, Srinivasan L, Shah S, et al. Mycobacterium tuberculosis infection of dendritic cells leads to partially caspase-1/11-independent IL-1β and IL-18 secretion but not to pyroptosis. PLoS One, 2012, 7(7):e40722. doi:10.1371/journal.pone.0040722.
[25]	Krishnan N, Robertson BD, Thwaites G. Pathways of IL-1β secretion by macrophages infected with clinical Mycobacterium tuberculosis strains. Tuberculosis (Edinb), 2013, 93(5):538-547. doi:10.1016/j.tube.2013.05.002.
[26]	Gringhuis SI, Kaptein TM, Wevers BA, et al. Dectin-1 is an extracellular pathogen sensor for the induction and processing of IL-1β via a noncanonical caspase-8 inflammasome. Nat Immunol, 2012, 13(3):246-254. doi:10.1038/ni.2222. pmid: 22267217
[27]	Rivers-Auty J, Daniels MJD, Colliver I, et al. Redefining the ancestral origins of the interleukin-1 superfamily. Nat Commun, 2018, 9 (1):1156. doi:10.1038/s41467-018-03362-1. pmid: 29559685
[28]	Priestle JP, Schar HP, Grutter MG. Crystal-Structure of the Cytokine Interleukin-1-β. Embo J, 1988, 7(2):339-343. doi:10.1002/j.1460-2075.1988.tb02818.x. pmid: 3259176
[29]	Ren XM, Gelinas AD, Von Carlowitz I, et al. Structural basis for IL-1 alpha recognition by a modified DNA aptamer that specifically inhibits IL-1 alpha signaling. Nat Commun, 2017, 8(1):810. doi:10.1038/s41467-017-00864-2.
[30]	Mosley B, Urdal DL, Prickett KS, et al. The interleukin-1 receptor binds the human interleukin-1 alpha precursor but not the interleukin-1 beta precursor. J Biol Chem, 1987, 262(7):2941-2944. doi:https://doi.org/10.1016/S0021-9258(18)61450-4. pmid: 2950091
[31]	Cohen I, Rider P, Vornov E, et al. IL-1 α is a DNA damage sensor linking genotoxic stress signaling to sterile inflammation and innate immunity. Sci Rep, 2015, 5:14756. doi:10.1038/srep14756. pmid: 26439902
[32]	Chiu JW, Binte Hanafi Z, Chew LCY, et al. IL-1α Processing, Signaling and Its Role in Cancer Progression. Cells, 2021, 10(1):92. doi:10.3390/cells10010092.
[33]	Stevenson FT, Bursten SL, Fanton C, et al. The 31-Kda Precursor of Interleukin-1-Alpha Is Myristoylated on Specific Lysines within the 16-Kda N-Terminal Propiece. Proc Natl Acad Sci U S A., 1993, 90(15):7245-7249. doi:10.1073/pnas.90.15.7245.
[34]	Dinarello CA. Immunological and inflammatory functions of the interleukin-1 family. Annu Rev Immunol, 2009, 27:519-550. doi:10.1146/annurev.immunol.021908.132612. pmid: 19302047
[35]	Fettelschoss A, Kistowska M, Leibundgut-Landmann S, et al. Inflammasome activation and IL-1β target IL-1α for secretion as opposed to surface expression. Proc Natl Acad Sci U S A., 2011, 108(44):18055-18060. doi:10.1073/pnas.1109176108.
[36]	Mandinova A, Soldi R, Graziani I, et al. S100A13 mediates the copper-dependent stress-induced release of IL-1α from both human U937 and murine NIH 3T3 cells. J Cell Sci, 2003, 116(13):2687-2696. doi:10.1242/jcs.00471.
[37]	Nickel W. The mystery of nonclassical protein secretion-A current view on cargo proteins and potential export routes. Eur J Biochem, 2003, 270(10):2109-2119. doi:10.1046/j.1432-1033.2003.03577.x.
[38]	Prudovsky I, Mandinova A, Soldi R, et al. The non-classical export routes: FGF1 and IL-1α point the way. J Cell Sci, 2003, 116(24):4871-4881. doi:10.1242/jcs.00872.
[39]	Andrei C, Margiocco P, Poggi A, et al. Phospholipases C and A2 control lysosome-mediated IL-1β secretion implications for inflammatory processes. Proc Natl Acad Sci U S A., 2004, 101(26):9745-9750. doi:10.1073/pnas.0308558101.
[40]	Andrei C, Dazzi C, Lotti L, et al. The secretory route of the leaderless protein interleukin 1β involves exocytosis of endolysosome-related vesicles. Mol Biol Cell, 1999, 10(5):1463-1475. doi:10.1091/mbc.10.5.1463. pmid: 10233156
[41]	Qu Y, Franchi L, Nunez G, et al. Nonclassical IL-1β Secretion Stimulated by P2X7 Receptors Is Dependent on Inflammasome Activation and Correlated with Exosome Release in Murine Macrophages. J Immunol, 2007, 179(3):1913-1925. doi:10.4049/jimmunol.179.3.1913.
[42]	Evavold CL, Ruan J, Tan Y, et al. The Pore-Forming Protein Gasdermin D Regulates Interleukin-1 Secretion from Living Macrophages. Immunity, 2018, 48(1):35-44.e6. doi:10.1016/j.immuni.2017.11.013. pmid: 29195811
[43]	Xia SY, Zhang ZB, Magupalli VG, et al. Gasdermin D pore structure reveals preferential release of mature interleukin-1. Nature, 2021, 593(7860):607-611. doi:10.1038/s41586-021-03478-3.
[44]	Sugawara I, Yamada H, Hua S, et al. Role of interleukin (IL)-1 type 1 receptor in mycobacterial infection. Microbiol Immunol, 2001, 45(11):743-750. doi:10.1111/j.1348-0421.2001.tb01310.x. pmid: 11791667
[45]	Yamada H, Mizumo S, Horai R, et al. Protective role of interleukin-1 in mycobacterial infection in IL-1 α/β double-knockout mice. Lab Invest, 2000, 80(5):759-767. doi:10.1038/labinvest.3780079. pmid: 10830786
[46]	Juffermans NP, Florquin S, Camoglio L, et al. Interleukin-1 signaling is essential for host defense during murine pulmonary tuberculosis. J Infect Dis, 2000, 182(3):902-908. doi:10.1086/315771. pmid: 10950787
[47]	Di Paolo NC, Shafiani S, Day T, et al. Interdependence between Interleukin-1 and Tumor Necrosis Factor Regulates TNF-Dependent Control of Mycobacterium tuberculosis Infection. Immunity, 2015, 43(6):1125-1136. doi:10.1016/j.immuni.2015.11.016.
[48]	Moorlag S, Khan N, Novakovic B, et al. β-Glucan Induces Protective Trained Immunity against Mycobacterium tuberculosis Infection: A Key Role for IL-1. Cell Rep, 2020, 31(7):107634. doi:10.1016/j.celrep.2020.107634.
[49]	Lovey A, Verma S, Kaipilyawar V, et al. Early alveolar macrophage response and IL-1R-dependent T cell priming determine transmissibility of Mycobacterium tuberculosis strains. Nat Commun, 2022, 13(1):884. doi:10.1038/s41467-022-28506-2.
[50]	Lee MR, Chang LY, Chang CH, et al. Differed IL-1 β Response between Active TB and LTBI Cases by Ex Vivo Stimulation of Human Monocyte-Derived Macrophage with TB-Specific Antigen. Dis Markers, 2019, 2019:7869576. doi:10.1155/2019/7869576.
[51]	Sousa J, Ca B, Maceiras AR, et al. Mycobacterium tuberculosis associated with severe tuberculosis evades cytosolic surveillance systems and modulates IL-1β production. Nat Commun, 2020, 11(1):1949. doi:10.1038/s41467-020-15832-6.
[52]	Mishra BB, Rathinam VA, Martens GW, et al. Nitric oxide controls the immunopathology of tuberculosis by inhibiting NLRP 3 inflammasome-dependent processing of IL-1beta. Nat Immunol, 2013, 14(1):52-60. doi:10.1038/ni.2474.
[53]	Laval T, Chaumont L, Demangel C. Not too fat to fight: The emerging role of macrophage fatty acid metabolism in immunity to Mycobacterium tuberculosis. Immunol Rev, 2021, 301(1):84-97. doi:10.1111/imr.12952.
[54]	Mayer-Barber KD, Andrade BB, Oland SD, et al. Host-directed therapy of tuberculosis based on interleukin-1 and type I interferon crosstalk. Nature, 2014, 511(7507):99-103. doi:10.1038/nature13489.
[55]	Gleeson LE, Sheedy FJ, Palsson-Mcdermott EM, et al. Cutting Edge: Mycobacterium tuberculosis Induces Aerobic Glycolysis in Human Alveolar Macrophages That Is Required for Control of Intracellular Bacillary Replication. J Immunol, 2016, 196(6):2444-2449. doi:10.4049/jimmunol.1501612. pmid: 26873991
[56]	Hackett EE, Charles-Messance H, O’leary SM, et al. Mycobacterium tuberculosis Limits Host Glycolysis and IL-1β by Restriction of PFK-M via MicroRNA-21. Cell Rep, 2020, 30(1):124-136 e4. doi:10.1016/j.celrep.2019.12.015. pmid: 31914380
[57]	Shi L, Salamon H, Eugenin EA, et al. Infection with Mycobacterium tuberculosis induces the Warburg effect in mouse lungs. Sci Rep, 2015, 5:18176. doi:10.1038/srep18176.
[58]	Lachmandas E, Beigier-Bompadre M, Cheng SC, et al. Rewiring cellular metabolism via the AKT/mTOR pathway contributes to host defence against Mycobacterium tuberculosis in human and murine cells. Eur J Immunol, 2016, 46(11):2574-2586. doi:10.1002/eji.201546259. pmid: 27624090
[59]	Tannahill GM, Curtis AM, Adamik J, et al. Succinate is an inflammatory signal that induces IL-1β through HIF-1α. Nature, 2013, 496(7444):238-242. doi:10.1038/nature11986.
[60]	Palsson-Mcdermott EM, Curtis AM, Goel G, et al. Pyruvate kinase M2 regulates Hif-1α activity and IL-1β induction and is a critical determinant of the warburg effect in LPS-activated macrophages. Cell Metab, 2015, 21(1):65-80. doi:10.1016/j.cmet.2014.12.005. pmid: 25565206
[61]	Braverman J, Sogi KM, Benjamin D, et al. HIF-1α Is an Essential Mediator of IFN-γ-Dependent Immunity to Mycobacterium tuberculosis. J Immunol, 2016, 197(4):1287-1297. doi:10.4049/jimmunol.1600266. pmid: 27430718
[62]	Escoll P, Buchrieser C. Metabolic reprogramming: an innate cellular defence mechanism against intracellular bacteria? Curr Opin Immunol, 2019, 60:117-123. doi:10.1016/j.coi.2019.05.009. pmid: 31247377
[63]	Mills EL, Kelly B, Logan A, et al. Succinate Dehydrogenase Supports Metabolic Repurposing of Mitochondria to Drive Inflammatory Macrophages. Cell, 2016, 167(2):457-470.e13. doi:10.1016/j.cell.2016.08.064. pmid: 27667687
[64]	Newsholme P, Curi R, Pithon Curi TC, et al. Glutamine metabolism by lymphocytes, macrophages, and neutrophils: its importance in health and disease. J Nutr Biochem, 1999, 10(6):316-324. doi:10.1016/s0955-2863(99)00022-4. pmid: 15539305
[65]	Cruzat V, Macedo Rogero M, Noel Keane K, et al. Glutamine: Metabolism and Immune Function, Supplementation and Clinical Translation. Nutrients, 2018, 10(11):1564. doi:10.3390/nu10111564.
[66]	Jiang QK, Qiu YP, Kurland IJ, et al. Glutamine Is Required for M1-like Polarization of Macrophages in Response to Mycobacterium tuberculosis Infection. Mbio, 2022, 13(4). doi:10.1128/mbio.01274-22.
[67]	Cordes T, Metallo CM. Itaconate Alters Succinate and Coenzyme A Metabolism via Inhibition of Mitochondrial Complex Ⅱ and Methylmalonyl-CoA Mutase. Metabolites, 2021, 11(2):117. doi:10.3390/metabo11020117.
[68]	Lampropoulou V, Sergushichev A, Bambouskova M, et al. Itaconate Links Inhibition of Succinate Dehydrogenase with Macrophage Metabolic Remodeling and Regulation of Inflammation. Cell Metab, 2016, 24(1):158-166. doi:10.1016/j.cmet.2016.06.004. pmid: 27374498
[69]	Bambouskova M, Gorvel L, Lampropoulou V, et al. Electrophilic properties of itaconate and derivatives regulate the IkappaBzeta-ATF 3 inflammatory axis. Nature, 2018, 556(7702):501-504. doi:10.1038/s41586-018-0052-z.
[70]	Mills EL, Ryan DG, Prag HA, et al. Itaconate is an anti-inflammatory metabolite that activates Nrf 2 via alkylation of KEAP1. Nature, 2018, 556(7699):113-117. doi:10.1038/nature25986.
[71]	He L, Weber KJ, Schilling JD. Glutamine Modulates Macrophage Lipotoxicity. Nutrients, 2016, 8(4):215. doi:10.3390/nu8040215. pmid: 27077881
[72]	Serhan CN, Chiang N, Van Dyke TE. Resolving inflammation: dual anti-inflammatory and pro-resolution lipid mediators. Nat Rev Immunol, 2008, 8(5):349-361. doi:10.1038/nri2294. pmid: 18437155
[73]	Chen M, Divangahi M, Gan H, et al. Lipid mediators in innate immunity against tuberculosis: opposing roles of PGE2 and LXA 4 in the induction of macrophage death. J Exp Med, 2008, 205(12):2791-2801. doi:10.1084/jem.20080767.
[74]	Travar M, Petkovic M, Verhaz A. Type Ⅰ, Ⅱ, and Ⅲ Interferons: Regulating Immunity to Mycobacterium tuberculosis Infection. Arch Immunol Ther Exp (Warsz), 2016, 64(1):19-31. doi:10.1007/s00005-015-0365-7.
[75]	Pestka S, Krause CD, Walter MR. Interferons, interferon-like cytokines, and their receptors. Immunol Rev, 2004, 202:8-32. doi:10.1111/j.0105-2896.2004.00204.x. pmid: 15546383
[76]	Kotenko SV, Gallagher G, Baurin VV, et al. IFN-λs mediate antiviral protection through a distinct class Ⅱ cytokine receptor complex. Nat Immunol, 2003, 4(1):69-77. doi:10.1038/ni875. pmid: 12483210
[77]	Sheppard P, Kindsvogel W, Xu WF, et al. IL-28, IL-29 and their class Ⅱ cytokine receptor IL-28R. Nat Immunol, 2003, 4(1):63-68. doi:10.1038/ni873. pmid: 12469119
[78]	Mayer-Barber KD, Andrade BB, Barber DL, et al. Innate and adaptive interferons suppress IL-1α and IL-1β production by distinct pulmonary myeloid subsets during Mycobacterium tuberculosis infection. Immunity, 2011, 35(6):1023-1034. doi:10.1016/j.immuni.2011.12.002. pmid: 22195750
[79]	Antonelli LR, Gigliotti Rothfuchs A, Goncalves R, et al. Intranasal Poly-IC treatment exacerbates tuberculosis in mice through the pulmonary recruitment of a pathogen-permissive monocyte/macrophage population. J Clin Invest, 2010, 120(5):1674-1682. doi:10.1172/JCI40817. pmid: 20389020
[80]	Clay H, Volkman HE, Ramakrishnan L. Tumor necrosis factor signaling mediates resistance to mycobacteria by inhibiting bacterial growth and macrophage death. Immunity, 2008, 29(2):283-294. doi:10.1016/j.immuni.2008.06.011. pmid: 18691913
[81]	Chavez-Galan L, Vesin D, Segueni N, et al. Tumor Necrosis Factor and Its Receptors Are Crucial to Control Mycobacterium bovis Bacillus Calmette-Guerin Pleural Infection in a Murine Model. Am J Pathol, 2016, 186(9):2364-2377. doi:10.1016/j.ajpath.2016.05.015. pmid: 27456129

名称	主要来源	受体(别称)	共受体(别称)	活性形式	功能	文献参考
IL-1α	角质形成细胞、内皮细胞、上皮细胞、单核细胞、巨噬细胞、树突状细胞、B淋巴细胞	IL-1R1(IL-1RⅠ、CD121a)	IL-1R3(IL-1RAcP)	全长、裂解后	促炎性细胞因子、Th17型细胞应答	[12-13]
IL-1β	单核细胞、巨噬细胞、树突状细胞、B细胞、NK细胞	IL-1R1	IL-1R3	裂解后	促炎性细胞因子、Th17型细胞应答抗细菌感染	[12-13]
IL-1Ra	单核细胞、巨噬细胞、树突状细胞、中性粒细胞上皮细胞	IL-1R1	-	-	抗炎性细胞因子	[14]
IL-18	巨噬细胞、树突状细胞、中性粒细胞上皮细胞	IL-1R5(IL-18Rα、IL-1Rrp、IL-1Rrp1、CD218a)	IL-1R7(IL-18Rβ、IL-18RAcP、CD218b)	裂解后	促炎性细胞因子、Th1型细胞应答	[15-16]
IL-33	内皮细胞、上皮细胞、成纤维样细胞	IL-1R4(IL-33R、ST2)	IL-1R3	全长、裂解后	促炎性细胞因子、Th2型细胞应答	[17]
IL-36 (α/β/γ)	皮肤、肠道等组织中的上皮细胞,在单核细胞中被强烈诱导角质形成细胞	IL-1R6(IL-1Rrp2、IL-1RL2、IL-36R)	IL-1R3	裂解后	促炎性细胞因子	[18]
IL-36Ra	人血单核细胞、组织巨噬细胞、滑膜细胞、扁桃体B细胞、浆细胞、T细胞、肿瘤细胞以及皮肤、肾脏和肠道的上皮细胞B细胞、上皮细胞	IL-1R6	-	裂解后	抗炎性细胞因子	[18]
IL-37		IL-1R5	IL-1R8(SIGGIR、TIR8)、IL-1R1	全长、裂解后	抗炎性细胞因子	[19]
IL-38		IL-1R6	IL-1R9(IL-1RAPL1、TIGIRR-2)、IL-1R1	-	抗炎性细胞因子	[13]