IMMUNE NETWORK

The Korean Association of Immunobiologists (대한면역학회)
권호 표지
DOI QR코드

DOI QR Code

SOCS3 Attenuates Dexamethasone-Induced M2 Polarization by Down-Regulation of GILZ via ROS- and p38 MAPK-Dependent Pathways

  • Hana Jeong (Department of Biological Science, College of Science, Sungkyunkwan University) ;
  • Hyeyoung Yoon (Department of Biological Science, College of Science, Sungkyunkwan University) ;
  • Yerin Lee (Department of Biological Science, College of Science, Sungkyunkwan University) ;
  • Jun Tae Kim (Department of Biological Science, College of Science, Sungkyunkwan University) ;
  • Moses Yang (Department of Biological Science, College of Science, Sungkyunkwan University) ;
  • Gayoung Kim (Department of Biological Science, College of Science, Sungkyunkwan University) ;
  • Bom Jung (Department of Biological Science, College of Science, Sungkyunkwan University) ;
  • Seok Hee Park (Department of Biological Science, College of Science, Sungkyunkwan University) ;
  • Choong-Eun Lee (Department of Biological Science, College of Science, Sungkyunkwan University)
  • Received : 2021.10.20
  • Accepted : 2022.06.02
  • Published : 2022.08.31
Download PDF
⟨ Previous Next ⟩

Abstract

Suppressors of cytokine signaling (SOCS) have emerged as potential regulators of macrophage function. We have investigated mechanisms of SOCS3 action on type 2 macrophage (M2) differentiation induced by glucocorticoid using human monocytic cell lines and mouse bone marrow-derived macrophages. Treatment of THP1 monocytic cells with dexamethasone (Dex) induced ROS generation and M2 polarization promoting IL-10 and TGF-β production, while suppressing IL-1β, TNF-α and IL-6 production. SOCS3 over-expression reduced, whereas SOCS3 ablation enhanced IL-10 and TGF-β induction with concomitant regulation of ROS. As a mediator of M2 differentiation, glucocorticoid-induced leucine zipper (GILZ) was down-regulated by SOCS3 and up-regulated by shSOCS3. The induction of GILZ and IL-10 by Dex was dependent on ROS and p38 MAPK activity. Importantly, GILZ ablation led to the inhibition of ROS generation and anti-inflammatory cytokine induction by Dex. Moreover, GILZ knock-down negated the up-regulation of IL-10 production induced by shSOCS3 transduction. Our data suggest that SOCS3 targets ROS- and p38-dependent GILZ expression to suppress Dex-induced M2 polarization.

Keywords

Acknowledgement

This study is supported in part by grants # 2015R1A2A2A01003291, # 2015M2B2A9029226, # 2018R1A2B6002201 and 2022R1H1A2003471 from Korea Research Foundation. Hana Jeong is supported in part by the 2017 Global Ph.D. fellowship program.

References

  1. Sica A, Mantovani A. Macrophage plasticity and polarization: in vivo veritas. J Clin Invest 2012;122:787-795. https://doi.org/10.1172/JCI59643
  2. Benoit M, Desnues B, Mege JL. Macrophage polarization in bacterial infections. J Immunol 2008;181:3733-3739. https://doi.org/10.4049/jimmunol.181.6.3733
  3. Sanjabi S, Zenewicz LA, Kamanaka M, Flavell RA. Anti-inflammatory and pro-inflammatory roles of TGF-β, IL-10, and IL-22 in immunity and autoimmunity. Curr Opin Pharmacol 2009;9:447-453. https://doi.org/10.1016/j.coph.2009.04.008
  4. Coutinho AE, Chapman KE. The anti-inflammatory and immunosuppressive effects of glucocorticoids, recent developments and mechanistic insights. Mol Cell Endocrinol 2011;335:2-13. https://doi.org/10.1016/j.mce.2010.04.005
  5. Quax RA, Manenschijn L, Koper JW, Hazes JM, Lamberts SW, van Rossum EF, Feelders RA. Glucocorticoid sensitivity in health and disease. Nat Rev Endocrinol 2013;9:670-686. https://doi.org/10.1038/nrendo.2013.183
  6. Furst R, Schroeder T, Eilken HM, Bubik MF, Kiemer AK, Zahler S, Vollmar AM. MAPK phosphatase-1 represents a novel anti-inflammatory target of glucocorticoids in the human endothelium. FASEB J 2007;21:74-80. https://doi.org/10.1096/fj.06-6752com
  7. Ayroldi E, Riccardi C. Glucocorticoid-induced leucine zipper (GILZ): a new important mediator of glucocorticoid action. FASEB J 2009;23:3649-3658. https://doi.org/10.1096/fj.09-134684
  8. Berrebi D, Bruscoli S, Cohen N, Foussat A, Migliorati G, Bouchet-Delbos L, Maillot MC, Portier A, Couderc J, Galanaud P, et al. Synthesis of glucocorticoid-induced leucine zipper (GILZ) by macrophages: an anti-inflammatory and immunosuppressive mechanism shared by glucocorticoids and IL-10. Blood 2003;101:729-738. https://doi.org/10.1182/blood-2002-02-0538
  9. Abraham SM, Lawrence T, Kleiman A, Warden P, Medghalchi M, Tuckermann J, Saklatvala J, Clark AR. Antiinflammatory effects of dexamethasone are partly dependent on induction of dual specificity phosphatase 1. J Exp Med 2006;203:1883-1889. https://doi.org/10.1084/jem.20060336
  10. Kassel O, Sancono A, Kratzschmar J, Kreft B, Stassen M, Cato AC. Glucocorticoids inhibit MAP kinase via increased expression and decreased degradation of MKP-1. EMBO J 2001;20:7108-7116. https://doi.org/10.1093/emboj/20.24.7108
  11. Mittelstadt PR, Ashwell JD. Inhibition of AP-1 by the glucocorticoid-inducible protein GILZ. J Biol Chem 2001;276:29603-29610. https://doi.org/10.1074/jbc.M101522200
  12. Ayroldi E, Migliorati G, Bruscoli S, Marchetti C, Zollo O, Cannarile L, D'Adamio F, Riccardi C. Modulation of T-cell activation by the glucocorticoid-induced leucine zipper factor via inhibition of nuclear factor κB. Blood 2001;98:743-753. https://doi.org/10.1182/blood.V98.3.743
  13. Wang Y, Ma YY, Song XL, Cai HY, Chen JC, Song LN, Yang R, Lu J. Upregulations of glucocorticoidinduced leucine zipper by hypoxia and glucocorticoid inhibit proinflammatory cytokines under hypoxic conditions in macrophages. J Immunol 2012;188:222-229. https://doi.org/10.4049/jimmunol.1002958
  14. Bhattacharyya S, Brown DE, Brewer JA, Vogt SK, Muglia LJ. Macrophage glucocorticoid receptors regulate Toll-like receptor 4-mediated inflammatory responses by selective inhibition of p38 MAP kinase. Blood 2007;109:4313-4319. https://doi.org/10.1182/blood-2006-10-048215
  15. Vago JP, Galvao I, Negreiros-Lima GL, Teixeira LC, Lima KM, Sugimoto MA, Moreira IZ, Jones SA, Lang T, Riccardi C, et al. Glucocorticoid-induced leucine zipper modulates macrophage polarization and apoptotic cell clearance. Pharmacol Res 2020;158:104842.
  16. Hoppstadter J, Kessler SM, Bruscoli S, Huwer H, Riccardi C, Kiemer AK. Glucocorticoid-induced leucine zipper: a critical factor in macrophage endotoxin tolerance. J Immunol 2015;194:6057-6067. https://doi.org/10.4049/jimmunol.1403207
  17. Vago JP, Tavares LP, Garcia CC, Lima KM, Perucci LO, Vieira EL, Nogueira CR, Soriani FM, Martins JO, Silva PM, et al. The role and effects of GILZ in the context of inflammation resolution. J Immunol 2015;194:4940-4950. https://doi.org/10.4049/jimmunol.1401722
  18. Shuai K, Liu B. Regulation of JAK-STAT signalling in the immune system. Nat Rev Immunol 2003;3:900-911. https://doi.org/10.1038/nri1226
  19. Tamiya T, Kashiwagi I, Takahashi R, Yasukawa H, Yoshimura A. Suppressors of cytokine signaling (SOCS) proteins and JAK/STAT pathways: regulation of T-cell inflammation by SOCS1 and SOCS3. Arterioscler Thromb Vasc Biol 2011;31:980-985. https://doi.org/10.1161/ATVBAHA.110.207464
  20. Nakagawa R, Naka T, Tsutsui H, Fujimoto M, Kimura A, Abe T, Seki E, Sato S, Takeuchi O, Takeda K, et al. SOCS-1 participates in negative regulation of LPS responses. Immunity 2002;17:677-687. https://doi.org/10.1016/S1074-7613(02)00449-1
  21. Alexander WS, Starr R, Fenner JE, Scott CL, Handman E, Sprigg NS, Corbin JE, Cornish AL, Darwiche R, Owczarek CM, et al. SOCS1 is a critical inhibitor of interferon gamma signaling and prevents the potentially fatal neonatal actions of this cytokine. Cell 1999;98:597-608. https://doi.org/10.1016/S0092-8674(00)80047-1
  22. Whyte CS, Bishop ET, Ruckerl D, Gaspar-Pereira S, Barker RN, Allen JE, Rees AJ, Wilson HM. Suppressor of cytokine signaling (SOCS)1 is a key determinant of differential macrophage activation and function. J Leukoc Biol 2011;90:845-854. https://doi.org/10.1189/jlb.1110644
  23. Qin H, Holdbrooks AT, Liu Y, Reynolds SL, Yanagisawa LL, Benveniste EN. SOCS3 deficiency promotes M1 macrophage polarization and inflammation. J Immunol 2012;189:3439-3448. https://doi.org/10.4049/jimmunol.1201168
  24. Arnold CE, Whyte CS, Gordon P, Barker RN, Rees AJ, Wilson HM. A critical role for suppressor of cytokine signalling 3 in promoting M1 macrophage activation and function in vitro and in vivo. Immunology 2014;141:96-110. https://doi.org/10.1111/imm.12173
  25. Gordon P, Okai B, Hoare JI, Erwig LP, Wilson HM. SOCS3 is a modulator of human macrophage phagocytosis. J Leukoc Biol 2016;100:771-780. https://doi.org/10.1189/jlb.3A1215-554RR
  26. Kim GY, Jeong H, Yoon HY, Yoo HM, Lee JY, Park SH, Lee CE. Anti-inflammatory mechanisms of suppressors of cytokine signaling target ROS via NRF-2/thioredoxin induction and inflammasome activation in macrophages. BMB Rep 2020;53:640-645. https://doi.org/10.5483/BMBRep.2020.53.12.161
  27. Zhang X, Goncalves R, Mosser DM. The isolation and characterization of murine macrophages. Curr Protoc Immunol 2008;Chapter 14:Unit 14.1.
  28. Kim SH, Lee CE. Counter-regulation mechanism of IL-4 and IFN-a signal transduction through cytosolic retention of the pY-STAT6:pY-STAT2:p48 complex. Eur J Immunol 2011;41:467-472.
  29. Murray PJ, Allen JE, Biswas SK, Fisher EA, Gilroy DW, Goerdt S, Gordon S, Hamilton JA, Ivashkiv LB, Lawrence T, et al. Macrophage activation and polarization: nomenclature and experimental guidelines. Immunity 2014;41:14-20. https://doi.org/10.1016/j.immuni.2014.06.008
  30. Griess B, Mir S, Datta K, Teoh-Fitzgerald M. Scavenging reactive oxygen species selectively inhibits M2 macrophage polarization and their pro-tumorigenic function in part, via Stat3 suppression. Free Radic Biol Med 2020;147:48-60. https://doi.org/10.1016/j.freeradbiomed.2019.12.018
  31. Furst R, Zahler S, Vollmar AM. Dexamethasone-induced expression of endothelial mitogen-activated protein kinase phosphatase-1 involves activation of the transcription factors activator protein-1 and 3',5'-cyclic adenosine 5'-monophosphate response element-binding protein and the generation of reactive oxygen species. Endocrinology 2008;149:3635-3642. https://doi.org/10.1210/en.2007-1524
  32. Ayroldi E, Zollo O, Macchiarulo A, Di Marco B, Macchetti C, Riccardi C. GILZ inhibits Raf/ERK pathway by binding to Raf-1. Mol Cell Biol 2002;22:7929-7941. https://doi.org/10.1128/MCB.22.22.7929-7941.2002
  33. Oh J, Hur MW, Lee CE. SOCS1 protects protein tyrosine phosphatases by thioredoxin upregulation and attenuates Jaks to suppress ROS-mediated apoptosis. Oncogene 2009;28:3145-3156. https://doi.org/10.1038/onc.2009.169
  34. Jung SH, Kim SM, Lee CE. Mechanism of suppressors of cytokine signaling 1inhibition of EMT signaling through ROS regulation in colon cancer cells: suppression of Src leading to thioredoxin upregulation. Oncotarget 2016;7:62559-62571. https://doi.org/10.18632/oncotarget.11537
  35. Kim S, Kim SH, Lee CE. SOCS1 represses fractionated ionizing radiation-induced EMT signaling pathways through the counter-regulation of ROS scavenging and generating systems. Cell Physiol Biochem 2020;54:1026-1040. https://doi.org/10.33594/000000285
  36. Ryu JY, Oh J, Kim S, Kim WG, Jeong H, Ahn SA, Kim SH, Jang JY, Kim CW, Yoo BC, et al. SOCS1 counter-acts the ROS-mediated survival signals and promotes apoptosis with cell cycle modulation to increase radiosensitivity of colorectal cancer cells. BMB Rep 2022;55:198-203. https://doi.org/10.5483/BMBRep.2022.55.4.191
  37. Liu Y, Stewart KN, Bishop E, Marek CJ, Kluth DC, Rees AJ, Wilson HM. Unique expression of suppressor of cytokine signaling 3 is essential for classical macrophage activation in rodents in vitro and in vivo. J Immunol 2008;180:6270-6278. https://doi.org/10.4049/jimmunol.180.9.6270