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Int. J. Mol. Sci. 2019, 20(15), 3701;

Mast Cells May Regulate The Anti-Inflammatory Activity of IL-37
Laboratory of Molecular Immunopharmacology and Drug Discovery, Department of Immunology, Tufts University School of Medicine, Boston, MA 02111, USA
Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, Boston, MA 02111, USA
Department of Internal Medicine, Tufts University School of Medicine and Tufts Medical Center, Boston, MA 02111, USA
Immunology Division, Postgraduate Medical School, University of Chieti, 65100 Pescara, Italy
Author to whom correspondence should be addressed.
Received: 6 June 2019 / Accepted: 19 July 2019 / Published: 29 July 2019


Mast cells are unique immune cells involved in allergic reactions, but also in immunity and inflammation. Interleukin 37 (IL-37) has emerged as an important regulatory cytokine with ability to inhibit immune and inflammatory processes. IL-37 is made primarily by macrophages upon activation of toll-like receptors (TLR) leading to generation of mature IL-37 via the action of caspase 1. In this review, we advance the premise that mast cells could regulate the anti-inflammatory activity of the IL-37 via their secretion of heparin and tryptase. Extracellular IL-37 could either dimerize in the presence of heparin and lose biological activity, or be acted upon by proteases that can generate even more biologically active IL-37 forms. Molecules that could selectively inhibit the secretion of mast cell mediators may, therefore, be used together with IL-37 as novel therapeutic agents.
chemokines; cytokines; IL-37; inflammation; mast cells; neuropeptides

1. Mast Cells in Inflammation

Mast cells derive from bone marrow progenitors and mature perivascularly in all tissues [1], where they are involved in allergic reactions [2]. Mast cells also act as sensors of environmental stress [3].
In addition to allergens, mast cells are also stimulated by pathogens [4], drugs, foods, heavy metals, and “danger signals” [2], as well as certain neuropeptides including corticotropin-releasing hormone (CRH) [5], neurotensin (NT) [6] and substance P (SP) [7,8]. Both NT [9,10] and SP [11,12,13,14] are known to participate in inflammatory processes. Stimulated mast cells can secrete numerous bioactive mediators [15,16,17], utilizing different secretory pathways [18]. Some of these mediators are prestored in secretory granules such as histamine, tryptase and tumor necrosis factor (TNF) [19,20]; others are synthesized de novo and include leukotrienes, prostaglandins, chemokines (CCXL8, CCL2) and cytokines [20,21], that include pro- and anti-inflammatory members, [22]. Many mediators can be secreted from mast cells selectively without degranulation [23]. In particular, CRH stimulates cultured human mast cells to produce vascular endothelial growth factor (VEGF) without tryptase [5].
As a result, mast cells are not only critical for allergic reactions [2,24], but are also important in innate and acquired immunity [25,26], antigen presentation [27,28] and inflammation [29,30].

2. IL-37 as An Anti-Inflammatory Agent

The IL-1 family comprises of IL-1a, IL-1b, IL-18, IL-33, IL-36a, IL-36b, IL-36g, IL-37, and IL-38 [31]. Interleukin-37 (IL-37, formerly IL-1F7) belongs to the IL-1 family of cytokines [7,32,33] and is a natural suppressor of immunity and inflammation [21,34,35].
Five isoforms (a–e) have so far been identified [34]. The “b” isoform of IL-37 used here is the most commonly used, but the d isoform was also reported to inhibit the expression of pro-inflammatory cytokines in PBMCs [36]. A specific receptor has not yet been identified for IL-37. A number of studies reported that extracellular IL-37 binds to the alpha chain of the IL-18 receptor (IL-18Rα) [37,38], but with much lower binding affinity than that of IL-18 [39].
Both the precursor and mature IL-37 bind IL-18Rα [39]. In addition, IL-37 binds to an IL-18 binding protein (IL-18BP) [40], and to the decoy receptor 8 (IL-R8) [41] via which extracellular forms of IL-37 inhibit innate inflammation in vitro and in vivo [42]. Extracellularly, the IL-37 monomer is the active form involved in reducing innate immunity [43]; instead, homodimerization of IL-37 reduces its anti-inflammatory activity [44]. The precise inhibitory mechanism of action of IL-37 is presently not known. One possibility may be that it inhibits mammalian target of rapamycin (mTOR) [45] since this complex was reported to be involved in the stimulatory action of NT on human microglia [46]. Another possibility may be that IL-37 inhibits inflammasome activation as reported in murine aspergillosis [47].
There have been apparently contradicting findings of increased IL-37 in inflammatory states reported in the literature. For instance, IL-37 was reported to be increased in the brain and plasma of patients after ischemic stroke and protected them from inflammatory brain injury [48]. Other studies also showed elevated serum IL-37 concentration in patients with sepsis [49] and in ankylosing spondylitis [50]. Instead, a state of IL-37 deficiency has been reported in calcific aortic stenosis [51].
Increased gene expression of IL-37 was associated with suppression of IL-1β and IL-6 production from peripheral blood mononuclear cells (PBMCs) from subjects with systemic inflammatory diseases [22,50,52,53,54,55]. IL-37 has been reported to inhibit the generation of pro-inflammatory cytokines in vitro [56], as well as in vivo [57], but apparently require the IL-1 family decoy receptor IL-1R8 [58].

3. Mast Cell-Derived Heparin and Tryptase May Regulate IL-37

IL-37 is made primarily by macrophages in response to toll-like receptor (TLR) activation, following which, an IL-37 precursor (pro-IL-37) is cleaved by caspase-1 into mature IL-37. Some of this IL-37 enters the nucleus while the rest is released along with pro-IL-37 outside the cells [59] where both are biologically active. It was recently reported that extracellular IL-37 is active as the monomer, while binding to heparin promotes its homodimerization, with the IL-37 dimers blocking the activity of the IL-37 monomer [43]. Extracellular proteases, hypothesized to be secreted by macrophages, can process pro-IL-37 into a much more biologically active form as shown for recombinant IL-37b with the N-terminus Val46 (V46-218) [60].
Mast cells are the richest source of heparin [61] and the only source of tryptase [62] in the body. Mast cells could regulate the anti-inflammatory activity of IL-37 in different ways (Figure 1). Heparin will inhibit the action of IL-37 by promoting the creation of homodimers [43]. Moreover, heparin would stabilize the tryptase homotetramer that would promote inflammation via activation of protease-activated receptors (PAR) [63]. Instead, tryptase monomers could generate mature, superactive IL-37 [60], in a method analogous to what had been reported for IL-33 [64,65].

4. Conclusions

We believe that the ratio of IL-1 to IL-37 is a determining factor in inflammatory diseases. Several drugs targeting IL-1β or its soluble IL-1R are available for treating inflammatory conditions [66], but there is still a need for more effective management of inflammation. IL-37 would be superior to other biologics beacause it is capable of inhibiting the generation of both cytokines and chemokines. IL-37 may also be administered together with other natural molecules [67,68], such as the flavonoid tetramethoxyluteolin, which has been reported to inhibit mast cell release of cytokines [8,69].


This research received no external funding.

Conflicts of Interest

The authors declare no conflict of interest.


CRHcorticotropin releasing hormone
CXCL8chemokine (C-X-C Motif) ligand 8
DAMPsdamage-associated molecular patterns
PBMCsperipheral blood-derived mononuclear cells
PARprotease-activated receptors
SPsubstance P
TNFtumor necrosis factor


  1. Galli, S.J.; Borregaard, N.; Wynn, T.A. Phenotypic and functional plasticity of cells of innate immunity: Macrophages, mast cells and neutrophils. Nat. Immunol. 2011, 12, 1035–1044. [Google Scholar] [CrossRef] [PubMed]
  2. Theoharides, T.C.; Valent, P.; Akin, C. Mast Cells, Mastocytosis, and Related Disorders. N. Engl. J. Med. 2015, 373, 163–172. [Google Scholar] [CrossRef] [PubMed]
  3. Theoharides, T.C. Neuroendocrinology of mast cells: Challenges and controversies. Exp. Dermatol. 2017, 26, 751–759. [Google Scholar] [CrossRef] [PubMed]
  4. Franza, L.; Carusi, V.; Altamura, S.; Gasbarrini, A.; Caraffa, A.; Kritas, S.K.; Ronconi, G.; Gallenga, C.E.; Di, V.F.; Pandolfi, F. Gut microbiota and immunity in common variable immunodeficiency: Crosstalk with pro-inflammatory cytokines. J. Biol. Regul. Homeost. Agents 2019, 33, 315–319. [Google Scholar] [PubMed]
  5. Cao, J.; Papadopoulou, N.; Kempuraj, D.; Boucher, W.S.; Sugimoto, K.; Cetrulo, C.L.; Theoharides, T.C. Human mast cells express corticotropin-releasing hormone (CRH) receptors and CRH leads to selective secretion of vascular endothelial growth factor. J. Immunol. 2005, 174, 7665–7675. [Google Scholar] [CrossRef] [PubMed]
  6. Donelan, J.; Boucher, W.; Papadopoulou, N.; Lytinas, M.; Papaliodis, D.; Theoharides, T.C. Corticotropin-releasing hormone induces skin vascular permeability through a neurotensin-dependent process. Proc. Natl. Acad. Sci. USA 2006, 103, 7759–7764. [Google Scholar] [CrossRef] [PubMed]
  7. Theoharides, T.C.; Zhang, B.; Kempuraj, D.; Tagen, M.; Vasiadi, M.; Angelidou, A.; Alysandratos, K.D.; Kalogeromitros, D.; Asadi, S.; Stavrianeas, N.; et al. IL-33 augments substance P-induced VEGF secretion from human mast cells and is increased in psoriatic skin. Proc. Natl. Acad. Sci. USA 2010, 107, 4448–4453. [Google Scholar] [CrossRef]
  8. Taracanova, A.; Tsilioni, I.; Conti, P.; Norwitz, E.R.; Leeman, S.E.; Theoharides, T.C. Substance P and IL-33 administered together stimulate a marked secretion of IL-1beta from human mast cells, inhibited by methoxyluteolin. Proc. Natl. Acad. Sci. USA 2018, 115, E9381–E9390. [Google Scholar] [CrossRef]
  9. Mustain, W.C.; Rychahou, P.G.; Evers, B.M. The role of neurotensin in physiologic and pathologic processes. Curr. Opin. Endocrinol. Diabetes Obes. 2011, 18, 75–82. [Google Scholar] [CrossRef]
  10. Caceda, R.; Kinkead, B.; Nemeroff, C.B. Neurotensin: Role in psychiatric and neurological diseases. Peptides 2006, 27, 2385–2404. [Google Scholar] [CrossRef]
  11. Mashaghi, A.; Marmalidou, A.; Tehrani, M.; Grace, P.M.; Pothoulakis, C.; Dana, R. Neuropeptide substance P and the immune response. Cell Mol. Life Sci. 2016, 73, 4249–4264. [Google Scholar] [CrossRef] [PubMed]
  12. O’Connor, T.M.; O’Connell, J.; O’Brien, D.I.; Goode, T.; Bredin, C.P.; Shanahan, F. The role of substance P in inflammatory disease. J. Cell Physiol. 2004, 201, 167–180. [Google Scholar] [CrossRef] [PubMed]
  13. Hokfelt, T.; Pernow, B.; Wahren, J. Substance P: A pioneer amongst neuropeptides. J. Intern. Med. 2001, 249, 27–40. [Google Scholar] [CrossRef] [PubMed]
  14. Douglas, S.D.; Leeman, S.E. Neurokinin-1 receptor: Functional significance in the immune system in reference to selected infections and inflammation. Ann. N. Y. Acad. Sci. 2011, 1217, 83–95. [Google Scholar] [CrossRef] [PubMed]
  15. Mukai, K.; Tsai, M.; Saito, H.; Galli, S.J. Mast cells as sources of cytokines, chemokines, and growth factors. Immunol. Rev. 2018, 282, 121–150. [Google Scholar] [CrossRef] [PubMed]
  16. Theoharides, T.C.; Kalogeromitros, D. The critical role of mast cells in allergy and inflammation. Ann. N. Y. Acad. Sci. 2006, 1088, 78–99. [Google Scholar] [CrossRef] [PubMed]
  17. Wernersson, S.; Pejler, G. Mast cell secretory granules: Armed for battle. Nat. Rev. Immunol. 2014, 14, 478–494. [Google Scholar] [CrossRef] [PubMed]
  18. Xu, H.; Bin, N.R.; Sugita, S. Diverse exocytic pathways for mast cell mediators. Biochem. Soc. Trans. 2018, 46, 235–247. [Google Scholar] [CrossRef]
  19. Gordon, J.R.; Galli, S.J. Mast cells as a source of both preformed and immunologically inducible TNF-a/cachectin. Nature 1990, 346, 274–276. [Google Scholar] [CrossRef]
  20. Zhang, B.; Alysandratos, K.D.; Angelidou, A.; Asadi, S.; Sismanopoulos, N.; Delivanis, D.A.; Weng, Z.; Miniati, A.; Vasiadi, M.; Katsarou-Katsari, A.; et al. Human mast cell degranulation and preformed TNF secretion require mitochondrial translocation to exocytosis sites: Relevance to atopic dermatitis. J. Allergy Clin. Immunol. 2011, 127, 1522–1531. [Google Scholar] [CrossRef]
  21. Caraffa, A.; Conti, C.; Ovidio, D.; Gallenga, C.E.; Tettamanti, L.; Mastrangelo, F.; Ronconi, G.; Kritas, S.K.; Conti, P. New concepts in neuroinflammation: Mast cells pro-inflammatory and anti-inflammatory cytokine mediators. J. Biol. Regul. Homeost. Agents 2018, 32, 449–454. [Google Scholar]
  22. Gallenga, C.E.; Pandolfi, F.; Caraffa, A.; Kritas, S.K.; Ronconi, G.; Toniato, E.; Martinotti, S.; Conti, P. Interleukin-1 family cytokines and mast cells: Activation and inhibition. J. Biol. Regul. Homeost. Agents 2019, 33, 1–6. [Google Scholar]
  23. Theoharides, T.C.; Kempuraj, D.; Tagen, M.; Conti, P.; Kalogeromitros, D. Differential release of mast cell mediators and the pathogenesis of inflammation. Immunol. Rev. 2007, 217, 65–78. [Google Scholar] [CrossRef]
  24. Beaven, M.A. Our perception of the mast cell from Paul Ehrlich to now. Eur. J. Immunol. 2009, 39, 11–25. [Google Scholar] [CrossRef]
  25. Toniato, E.; Frydas, I.; Robuffo, I.; Ronconi, G.; Caraffa, A.; Kritas, S.K.; Conti, P. Activation and inhibition of adaptive immune response mediated by mast cells. J. Biol. Regul. Homeost. Agents 2017, 31, 543–548. [Google Scholar] [PubMed]
  26. Marone, G.; Galli, S.J.; Kitamura, Y. Probing the roles of mast cells and basophils in natural and acquired immunity, physiology and disease. Trends Immunol. 2002, 23, 425–427. [Google Scholar] [CrossRef]
  27. Gong, J.; Yang, N.S.; Croft, M.; Weng, I.C.; Sun, L.; Liu, F.T.; Chen, S.S. The antigen presentation function of bone marrow-derived mast cells is spatiotemporally restricted to a subset expressing high levels of cell surface FcepsilonRI and MHC II. BMC Immunol. 2010, 11, 34. [Google Scholar] [CrossRef]
  28. Carroll-Portillo, A.; Cannon, J.L.; te Riet, J.; Holmes, A.; Kawakami, Y.; Kawakami, T.; Cambi, A.; Lidke, D.S. Mast cells and dendritic cells form synapses that facilitate antigen transfer for T cell activation. J. Cell Biol. 2015, 210, 851–864. [Google Scholar] [CrossRef] [PubMed]
  29. Galli, S.J.; Tsai, M.; Piliponsky, A.M. The development of allergic inflammation. Nature 2008, 454, 445–454. [Google Scholar] [CrossRef]
  30. Theoharides, T.C.; Alysandratos, K.D.; Angelidou, A.; Delivanis, D.A.; Sismanopoulos, N.; Zhang, B.; Asadi, S.; Vasiadi, M.; Weng, Z.; Miniati, A.; et al. Mast cells and inflammation. Biochim. Biophys. Acta 2010, 1822, 21–33. [Google Scholar] [CrossRef] [PubMed]
  31. Dinarello, C.A. The IL-1 family and inflammatory diseases. Clin. Exp. Rheumatol. 2002, 20, S1–S13. [Google Scholar]
  32. Vasiadi, M.; Therianou, A.; Sideri, K.; Smyrnioti, M.; Sismanopoulos, N.; Delivanis, D.A.; Asadi, S.; Katsarou-Katsari, A.; Petrakopoulou, T.; Theoharides, A.; et al. Increased serum CRH levels with decreased skin CRHR-1 gene expression in psoriasis and atopic dermatitis. J. Allergy Clin. Immunol. 2012, 129, 1410–1413. [Google Scholar] [CrossRef]
  33. Konnikov, N.; Pincus, S.H.; Dinarello, C.A. Elevated plasma interleukin-1 levels in humans following ultraviolet light therapy for psoriasis. J. Invest. Dermatol. 1989, 92, 235–239. [Google Scholar] [CrossRef]
  34. Dinarello, C.A.; Bufler, P. Interleukin-37. Semin. Immunol. 2013, 25, 466–468. [Google Scholar] [CrossRef]
  35. Tettamanti, L.; Kritas, S.K.; Gallenga, C.E.; D’Ovidio, C.; Mastrangelo, F.; Ronconi, G.; Caraffa, A.; Toniato, E.; Conti, P. IL-33 mediates allergy through mast cell activation, Potential inhibitory effect of certain cytokines. J. Biol. Regul. Homeost. Agents 2018, 32, 1061–1065. [Google Scholar]
  36. Zhao, M.; Li, Y.; Guo, C.; Wang, L.; Chu, H.; Zhu, F.; Li, Y.; Wang, X.; Wang, Q.; Zhao, W.; et al. IL-37 isoform D downregulates pro-inflammatory cytokines expression in a Smad3-dependent manner. Cell Death Dis. 2018, 9, 582. [Google Scholar] [CrossRef]
  37. Pan, G.; Risser, P.; Mao, W.; Baldwin, D.T.; Zhong, A.W.; Filvaroff, E.; Yansura, D.; Lewis, L.; Eigenbrot, C.; Henzel, W.J.; et al. IL-1H, an interleukin 1-related protein that binds IL-18 receptor/IL-1Rrp. Cytokine 2001, 13, 1–7. [Google Scholar] [CrossRef]
  38. Kumar, S.; Hanning, C.R.; Brigham-Burke, M.R.; Rieman, D.J.; Lehr, R.; Khandekar, S.; Kirkpatrick, R.B.; Scott, G.F.; Lee, J.C.; Lynch, F.J.; et al. Interleukin-1F7B (IL-1H4/IL-1F7) is processed by caspase-1 and mature IL-1F7B binds to the IL-18 receptor but does not induce IFN-gamma production. Cytokine 2002, 18, 61–71. [Google Scholar] [CrossRef]
  39. Jia, H.; Liu, J.; Han, B. Reviews of Interleukin-37: Functions, Receptors, and Roles in Diseases. Biomed. Res. Int. 2018, 2018, 3058640. [Google Scholar] [CrossRef]
  40. Bufler, P.; Azam, T.; Gamboni-Robertson, F.; Reznikov, L.L.; Kumar, S.; Dinarello, C.A.; Kim, S.H. A complex of the IL-1 homologue IL-1F7b and IL-18-binding protein reduces IL-18 activity. Proc. Natl. Acad. Sci. USA 2002, 99, 13723–13728. [Google Scholar] [CrossRef]
  41. Cavalli, G.; Justice, J.N.; Boyle, K.E.; D’Alessandro, A.; Eisenmesser, E.Z.; Herrera, J.J.; Hansen, K.C.; Nemkov, T.; Stienstra, R.; Garlanda, C.; et al. Interleukin 37 reverses the metabolic cost of inflammation, increases oxidative respiration, and improves exercise tolerance. Proc. Natl. Acad. Sci. USA 2017, 114, 2313–2318. [Google Scholar] [CrossRef]
  42. Dinarello, C.A.; Nold-Petry, C.; Nold, M.; Fujita, M.; Li, S.; Kim, S.; Bufler, P. Suppression of innate inflammation and immunity by interleukin-37. Eur. J. Immunol. 2016, 46, 1067–1081. [Google Scholar] [CrossRef]
  43. Eisenmesser, E.Z.; Gottschlich, A.; Redzic, J.S.; Paukovich, N.; Nix, J.C.; Azam, T.; Zhang, L.; Zhao, R.; Kieft, J.S.; The, E.; et al. Interleukin-37 monomer is the active form for reducing innate immunity. Proc. Natl. Acad. Sci. USA 2019, 116, 5514–5522. [Google Scholar] [CrossRef]
  44. Ellisdon, A.M.; Nold-Petry, C.A.; D’Andrea, L.; Cho, S.X.; Lao, J.C.; Rudloff, I.; Ngo, D.; Lo, C.Y.; Soares da Costa, T.P.; Perugini, M.A.; et al. Homodimerization attenuates the anti-inflammatory activity of interleukin-37. Sci. Immunol. 2017, 2, eaaj1548. [Google Scholar] [CrossRef]
  45. Li, T.T.; Zhu, D.; Mou, T.; Guo, Z.; Pu, J.L.; Chen, Q.S.; Wei, X.F.; Wu, Z.J. IL-37 induces autophagy in hepatocellular carcinoma cells by inhibiting the PI3K/AKT/mTOR pathway. Mol. Immunol. 2017, 87, 132–140. [Google Scholar] [CrossRef]
  46. Patel, A.B.; Tsilioni, I.; Leeman, S.E.; Theoharides, T.C. Neurotensin stimulates sortilin and mTOR in human microglia inhibitable by methoxyluteolin, a potential therapeutic target for autism. Proc. Natl. Acad. Sci. USA 2016, 113, E7049–E7058. [Google Scholar] [CrossRef]
  47. Moretti, S.; Bozza, S.; Oikonomou, V.; Renga, G.; Casagrande, A.; Iannitti, R.G.; Puccetti, M.; Garlanda, C.; Kim, S.; Li, S.; et al. IL-37 inhibits inflammasome activation and disease severity in murine aspergillosis. PLoS Pathog. 2014, 10, e1004462. [Google Scholar] [CrossRef]
  48. Zhang, S.R.; Nold, M.F.; Tang, S.C.; Bui, C.B.; Nold, C.A.; Arumugam, T.V.; Drummond, G.R.; Sobey, C.G.; Kim, H.A. IL-37 increases in patients after ischemic stroke and protects from inflammatory brain injury, motor impairment and lung infection in mice. Sci. Rep. 2019, 9, 6922. [Google Scholar] [CrossRef]
  49. Wang, Y.C.; Weng, G.P.; Liu, J.P.; Li, L.; Cheng, Q.H. Elevated serum IL-37 concentrations in patients with sepsis. Medicine 2019, 98, e14756. [Google Scholar] [CrossRef]
  50. Chen, B.; Huang, K.; Ye, L.; Li, Y.; Zhang, J.; Zhang, J.; Fan, X.; Liu, X.; Li, L.; Sun, J.; et al. Interleukin-37 is increased in ankylosing spondylitis patients and associated with disease activity. J. Transl. Med. 2015, 13, 36. [Google Scholar] [CrossRef]
  51. Zeng, Q.; Song, R.; Fullerton, D.A.; Ao, L.; Zhai, Y.; Li, S.; Ballak, D.B.; Cleveland, J.C., Jr.; Reece, T.B.; McKinsey, T.A.; et al. Interleukin-37 suppresses the osteogenic responses of human aortic valve interstitial cells in vitro and alleviates valve lesions in mice. Proc. Natl. Acad. Sci. USA 2017, 114, 1631–1636. [Google Scholar] [CrossRef]
  52. Ye, L.; Ji, L.; Wen, Z.; Zhou, Y.; Hu, D.; Li, Y.; Yu, T.; Chen, B.; Zhang, J.; Ding, L.; et al. IL-37 inhibits the production of inflammatory cytokines in peripheral blood mononuclear cells of patients with systemic lupus erythematosus: Its correlation with disease activity. J. Transl. Med. 2014, 12, 69. [Google Scholar] [CrossRef]
  53. Li, Y.; Wang, Z.; Yu, T.; Chen, B.; Zhang, J.; Huang, K.; Huang, Z. Increased expression of IL-37 in patients with Graves’ disease and its contribution to suppression of proinflammatory cytokines production in peripheral blood mononuclear cells. PLoS ONE 2014, 9, e107183. [Google Scholar] [CrossRef]
  54. Ye, L.; Jiang, B.; Deng, J.; Du, J.; Xiong, W.; Guan, Y.; Wen, Z.; Huang, K.; Huang, Z. IL-37 Alleviates Rheumatoid Arthritis by Suppressing IL-17 and IL-17-Triggering Cytokine Production and Limiting Th17 Cell Proliferation. J. Immunol. 2015, 194, 5110–5119. [Google Scholar] [CrossRef]
  55. Varvara, G.; Tettamanti, L.; Gallenga, C.E.; Caraffa, A.; D’Ovidio, C.; Mastrangelo, F.; Ronconi, G.; Kritas, S.K.; Conti, P. Stimulated mast cells release inflammatory cytokines: Potential suppression and therapeutical aspects. J. Biol. Regul. Homeost. Agents 2018, 32, 1355–1360. [Google Scholar]
  56. Abulkhir, A.; Samarani, S.; Amre, D.; Duval, M.; Haddad, E.; Sinnett, D.; Leclerc, J.M.; Diorio, C.; Ahmad, A. A protective role of IL-37 in cancer: A new hope for cancer patients. J. Leukoc. Biol. 2017, 101, 395–406. [Google Scholar] [CrossRef]
  57. Cavalli, G.; Koenders, M.; Kalabokis, V.; Kim, J.; Tan, A.C.; Garlanda, C.; Mantovani, A.; Dagna, L.; Joosten, L.A.; Dinarello, C.A. Treating experimental arthritis with the innate immune inhibitor interleukin-37 reduces joint and systemic inflammation. Rheumatology 2016, 55, 2220–2229. [Google Scholar] [CrossRef]
  58. Li, S.; Neff, C.P.; Barber, K.; Hong, J.; Luo, Y.; Azam, T.; Palmer, B.E.; Fujita, M.; Garlanda, C.; Mantovani, A.; et al. Extracellular forms of IL-37 inhibit innate inflammation in vitro and in vivo but require the IL-1 family decoy receptor IL-1R8. Proc. Natl. Acad. Sci. USA 2015, 112, 2497–2502. [Google Scholar] [CrossRef]
  59. Li, S.; mo-Aparicio, J.; Neff, C.P.; Tengesdal, I.W.; Azam, T.; Palmer, B.E.; Lopez-Vales, R.; Bufler, P.; Dinarello, C.A. Role for nuclear interleukin-37 in the suppression of innate immunity. Proc. Natl. Acad. Sci. USA 2019. [Google Scholar] [CrossRef]
  60. Cavalli, G.; Dinarello, C.A. Suppression of inflammation and acquired immunity by IL-37. Immunol. Rev. 2018, 281, 179–190. [Google Scholar] [CrossRef]
  61. Stevens, R.L.; Adachi, R. Protease-proteoglycan complexes of mouse and human mast cells and importance of their beta-tryptase-heparin complexes in inflammation and innate immunity. Immunol. Rev. 2007, 217, 155–167. [Google Scholar] [CrossRef]
  62. Schwartz, L.B. Tryptase, a mediator of human mast cells. J. Allergy Clin. Immunol. 1990, 86, 594–598. [Google Scholar] [CrossRef]
  63. Heuberger, D.M.; Schuepbach, R.A. Protease-activated receptors (PARs): Mechanisms of action and potential therapeutic modulators in PAR-driven inflammatory diseases. Thromb. J. 2019, 17, 4. [Google Scholar] [CrossRef]
  64. Lefrancais, E.; Duval, A.; Mirey, E.; Roga, S.; Espinosa, E.; Cayrol, C.; Girard, J.P. Central domain of IL-33 is cleaved by mast cell proteases for potent activation of group-2 innate lymphoid cells. Proc. Natl. Acad. Sci. USA 2014, 111, 15502–15507. [Google Scholar] [CrossRef]
  65. Lefrancais, E.; Cayrol, C. Mechanisms of IL-33 processing and secretion: Differences and similarities between IL-1 family members. Eur. Cytokine Netw. 2012, 23, 120–127. [Google Scholar]
  66. Dinarello, C.A.; Simon, A.; van der Meer, J.W. Treating inflammation by blocking interleukin-1 in a broad spectrum of diseases. Nat. Rev. Drug Discov. 2012, 11, 633–652. [Google Scholar] [CrossRef]
  67. Theoharides, T.C.; Kavalioti, M. Stress, inflammation and natural treatments. J. Biol. Regul. Homeost. Agents 2018, 32, 1345–1347. [Google Scholar]
  68. Mo, X.J.; Ye, X.Z.; Li, Y.P. Effects of euphorbia kansui on the serum levels of IL-6, TNF-alpha, NF-kappaB, sTNFR and IL-8 in patients with severe acute pancreatitis. J. Biol. Regul. Homeost. Agents 2019, 33, 469–475. [Google Scholar]
  69. Patel, A.B.; Theoharides, T.C. Methoxyluteolin Inhibits Neuropeptide-stimulated Proinflammatory Mediator Release via mTOR Activation from Human Mast Cells. J. Pharmacol. Exp. Ther. 2017, 361, 462–471. [Google Scholar] [CrossRef]
Figure 1. Diagrammatic representation of the role of mast cell-derived heparin in the regulation of the activity of IL-37. Activation of caspase 1 in macrophages, in response to TLR activation, leads to cleavage of pro-IL-37 to mature IL-37, both of which are secreted outside the cell and have anti-inflammatory activity. In the tissue microenvironment, mast cells secrete heparin, which interacts with IL-37 and promotes the formation of inactive homodimers. Mast cells also secrete the proteolytic enzyme tryptase, which exists as homotetramer bound to heparin and promotes inflammation by acting on protease-activated receptors (PAR). In the absence of heparin, biologically active tryptase monomers may be able to generate IL-37 forms with increased anti-inflammatory activity. Open arrows = activation; thin arrows = secretion; thick arrows = stimulation; T arrows = inhibition.
Figure 1. Diagrammatic representation of the role of mast cell-derived heparin in the regulation of the activity of IL-37. Activation of caspase 1 in macrophages, in response to TLR activation, leads to cleavage of pro-IL-37 to mature IL-37, both of which are secreted outside the cell and have anti-inflammatory activity. In the tissue microenvironment, mast cells secrete heparin, which interacts with IL-37 and promotes the formation of inactive homodimers. Mast cells also secrete the proteolytic enzyme tryptase, which exists as homotetramer bound to heparin and promotes inflammation by acting on protease-activated receptors (PAR). In the absence of heparin, biologically active tryptase monomers may be able to generate IL-37 forms with increased anti-inflammatory activity. Open arrows = activation; thin arrows = secretion; thick arrows = stimulation; T arrows = inhibition.
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