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Vol. 63 No. 10: Issue 10

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LPS-induced Src family kinases activity mediates IL-10 production through activation of STAT3 in peripheral blood mononuclear cells of patients with Behçet's Disease

https://doi.org/10.14715/cmb/2017.63.10.18
S. Irtegun Kandemir
Department of Medical Biology, Faculty of Medicine, Dicle University, Diyarbakir, Turkey
M. A. Tekin
Department of Medical Biology, Faculty of Medicine, Dicle University, Diyarbakir, Turkey
M. Bozkurt
Department of Physical Therapy and Rehabilitation, Faculty of Medicine, Dicle University, Diyarbakir, Turkey
A. Z. Dagli
Physical Therapy Clinic, Bitlis Government Hospital, Bitlis Turkey
S. Kalkanli-Tas
Department of Medical Biology, Faculty of Medicine, University of Health Sciences, Istanbul, Turkey

Corresponding Author(s) : S. Irtegun Kandemir

irtegunsevgi@hotmail.com

Cellular and Molecular Biology, Vol. 63 No. 10: Issue 10

Abstract

Behçet's disease (BD) is achronic inflammatory disorder characterized by recurrent oral and genital ulcers, uveitis and skin lesions. Although,the pathogenesis of BD remains poorly understood, excessive or dysregulatedcytokine production including IL-10 is associated with BD. Revealing the key molecular mechanism by which IL-10 expression is regulated is crucial to understanding the pathogenesis of BD. The aim of this study was to investigate whether Src family kinases (SFKs) are upstream mediators of STAT3/IL-10 pathway in peripheral blood mono nuclear cells(PBMCs) of active BD patients.Twenty active BD patients and twenty healthy subjects used as control were included in the study. PBMCs were isolated from total blood by density gradient centrifugation.Western blot and ELISA methods were applied to analyzelipopolysaccharide (LPS)-induced SFKs/STAT3/IL10 signaling pathway in BD.Inhibition of SFKs activity suppressed LPS-induced IL-10 production in PBMCs fromboth controls and active BD patients. Similarly, blockage of STAT3 activation abrogated LPS-induced IL-10 production. However, LPS-induced STAT3 activation required for IL-10 production was found to be dependent on SFKs activity as LPS-induced STAT3 phosphorylation was reduced by the inhibition of SFKs activity in PBMCs of active BD patients.SFKs activity is essential for LPS-induced STAT3/IL-10 pathway in PBMCs of active BD patients. Manipulation of the SFKs activity may offer a novel therapeutic approach for BD.

Keywords

Behçet's disease Src family kinases IL-10 STAT3 LPS.
Irtegun Kandemir, S., Tekin, M. A., Bozkurt, M., Dagli, A. Z., & Kalkanli-Tas, S. (2017). LPS-induced Src family kinases activity mediates IL-10 production through activation of STAT3 in peripheral blood mononuclear cells of patients with Behçet’s Disease. Cellular and Molecular Biology, 63(10), 116–121. https://doi.org/10.14715/cmb/2017.63.10.18
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References
  1. Alpsoy E. Behçet's disease: A comprehensive review with a focus on epidemiology, etiology and clinical features, and management of mucocutaneous lesions. Journal of Dermatology 2016; 43: 620"’32.
  2. Mat MC, Sevim A, Fresko I, Tüzün Y. Behçet's disease as a systemic disease. Clin Dermatol 2014; 32: 435"’42.
  3. Sakane T, Takeno M, Suzuki N, Inaba G. Behí‡et's disease. N Engl J Med 1999; 341: 1284"’91.
  4. Mazzoccoli G, Matarangolo A, Rubino R, Inglese M, De Cata A. Behçet syndrome: from pathogenesis to novel therapies. Clinical and experimental medicine 2016; 16: 1"’12.
  5. Verity DH, Marr JE, Ohno S, Wallace GR, Stanford MR. Behçet's disease, the Silk Road and HLA"B51: historical and geographical perspectives. HLA 1999; 54: 213"’20.
  6. Ombrello MJ, Kirino Y, de Bakker PI et al. Behçet disease-associated MHC class I residues implicate antigen binding and regulation of cell-mediated cytotoxicity. Proceedings of the National Academy of Sciences 2014; 111: 8867"’72.
  7. Hamzaoui A, Houman MH, Massouadia M. Contribution of Hla-B51 in the susceptibility and specific clinical features of Behcet's disease in Tunisian patients. European journal of internal medicine 2012; 23: 347"’49.
  8. Matos M, Xavier JM, Abrantes P et al. IL10 low-frequency variants in Behçet's disease patients. Int J Rheum Dis 2017; 20: 622"’27.
  9. Mizuki N, Meguro A, Ota M et al. Genome-wide association studies identify IL23R-IL12RB2 and IL10 as Behçet's disease susceptibility loci. Nat Genet 2010; 42: 703–6.
  10. Zhao C, Yang P, He H, et al. S-antigen specific T helper type 1 response is present in Behcet's disease. Mol Vis 2008; 14: 1456"’64.
  11. Oztas MO, Onder M, Gurer MA, Bukan N, Sancak B. Serum interleukin 18 and tumour necrosis factor"α levels are increased in Behcet's disease. Clinical and experimental dermatology 2005; 30: 61"’63.
  12. Zhou ZY, Chen SL, Shen N, Lu Y. Cytokines and Behcet's Disease. Autoimmunity Reviews 2012; 11: 699"’704.
  13. Irtegun S, Pektanc G, Akkurt ZM et al. Pharmacological Inactivation of Src Family Kinases Inhibits LPS-Induced TNF-α Production in PBMC of Patients with Behçet's Disease. Mediators of inflammation 2016; 2016.
  14. Cicioglu Aridogan B, Yildirim M Baysal V et al. Serum Levels of IL-4, IL-10, IL-12, IL-13 and IFN-Gamma in Behçet's Disease. The Journal of Dermatology 2003; 30: 602–7.
  15. Akman-Demir G, Tüzün E, Içöz S et al. Interleukin-6 in neuro-Behçet's disease: association with disease subsets and long-term outcome. Cytokine 2008; 44: 373–6.
  16. O'Garra A, Vieira PL, Vieira P, Goldfeld AE. IL-10-producing and naturally occurring CD4+ Tregs: limiting collateral damage. J Clin Invest 2004; 114: 1372"’8.
  17. Mizoguchi A, Mizoguchi E, Takedatsu H, Blumberg RS, Bhan AK. Chronic intestinal inflammatory condition generates IL-10-producing regulatory B cell subset characterized by CD1d upregulation. Immunity 2002; 16: 219"’30.
  18. Iyer SS, Ghaffari AA, Cheng G. Lipopolysaccharide-mediated IL-10 transcriptional regulation requires sequential induction of type I IFNs and IL-27 in macrophages. The Journal of Immunology 2010; 185: 6599"’607.
  19. Lu YC, Yeh WC, Ohashi PS. LPS/TLR4 signal transduction pathway. Cytokine 2008; 42: 145-51.
  20. Staples KJ, Smallie T, Williams LM et al. IL-10 induces IL-10 in primary human monocyte-derived macrophages via the transcription factor Stat3. J. Immunol 2007; 178: 4779"’85.
  21. Murray PJ. STAT3-mediated anti-inflammatory signalling. Biochemical Society Transactions 2006; 34: 1028"’31.
  22. Benkhart EM, Siedlar M, Wedel A, Werner T, Ziegler-Heitbrock HL. Role of Stat3 in lipopolysaccharide-induced IL-10 gene expression. The journal of Immunology 2000; 165: 1612"’17.
  23. Qi J, Yang Y, Hou S et al. Increased Notch pathway activation in Behcet's disease. Rheumatology 2014; 53: 810"’20.
  24. Tulunay A, Dozmorov MG, Ture-Ozdemir F et al. Activation of the JAK/STAT pathway in Behcet's Disease. Genes Immun 2015; 16: 170"’5.
  25. Saijo K, Schmedt C, Su IH et al. Essential role of Src-family protein tyrosine kinases in NF-[kappa] B activation during B cell development. Nature immunology 2003; 4: 274"’9.
  26. Meyn MA, Schreiner SJ, Dumitrescu TP, Nau GJ, Smithgall TE. SRC family kinase activity is required for murine embryonic stem cell growth and differentiation. Molecular pharmacology 2005; 68: 1320"’30.
  27. Elsberger B, Fullerton R, Zino S et al. Breast cancer patients' clinical outcome measures are associated with Src kinase family member expression. British journal of cancer 2010; 103: 899"’909.
  28. Flores"Borja F, Kabouridis PS, Jury EC, Isenberg DA, Mageed RA. Decreased Lyn expression and translocation to lipid raft signaling domains in B lymphocytes from patients with systemic lupus erythematosus. Arthritis & Rheumatology 2005; 52: 3955"’65.
  29. Napolitani G, Bortoletto N, Racioppi L, Lanzavecchia A, D'Oro U. Activation of src-family tyrosine kinases by LPS regulates cytokine production in dendritic cells by controlling AP-1 formation. Eur J Immunol 2003; 33: 2832"’41.
  30. Smolinska MJ, Horwood NJ, Page TH, Smallie T, Foxwell BMJ. Chemical inhibition of Src family kinases affects major LPS activated pathways in primary human macrophages. Molecular Imunology 2008; 45: 990-1000.
  31. Gong P, Angelini DJ, Yang S et al. TLR4 signaling is coupled to SRC family kinase activation, tyrosine phosphorylation of zonula adherens proteins, and opening of the paracellular pathway in human lung microvascular endothelia. Journal of Biological Chemistry 2008; 283: 13437-49.
  32. Laird AD, Li G, Moss KG et al. Src Family Kinase Activity Is Required for Signal Tranducer and Activator of Transcription 3 and Focal Adhesion Kinase Phosphorylation and Vascular Endothelial Growth Factor Signaling in Vivo and for Anchorage-dependent and -independent Growth of Human Tumor Cells. Molecular Cancer Therapeutics 2003; 2: 461"’69.
  33. Garcí­a"Hernández V, Flores"Maldonado C, Rincon"Heredia R et al. EGF regulates claudin"2 and"4 expression through Src and STAT3 in MDCK cells. Journal of cellular physiology 2015; 230: 105"’15.
  34. Bowman T, Broome MA, Sinibaldi D et al. Stat3-mediated Myc expression is required for Src transformation and PDGF-induced mitogenesis. Proceedings of the National Academy of Sciences 2001; 98: 7319"’24.
  35. Nagaraj NS, Smith JJ, Revetta F, Washington MK, Merchant NB. Targeted inhibition of SRC kinase signaling attenuates pancreatic tumorigenesis. Molecular cancer therapeutics 2010; 9: 2322"’32.
  36. Irtegun S, Wood RJ, Ormsby AR, Mulhern TD, Hatters DM. Tyrosine 416 is phosphorylated in the closed, repressed conformation of c-Src. PLoS One 2013; 8(7):e71035.
  37. International Study Group for Behçet disease. Criteria for diagnosis of Behçet's disease. Lancet 1990; 335: 1078"’80.
  38. Joyce DA, Gibbons DP, Green P et al. Two inhibitors of pro"inflammatory cytokine release, interleukin"10 and interleukin"4, have contrasting effects on release of soluble p75 tumor necrosis factor receptor by cultured monocytes. European journal of immunology 1994; 24: 2699"’705.
  39. Huang Y, Li T, Sane DC, Li L. IRAK1 serves as a novel regulator essential for lipopolysaccharide-induced interleukin-10 gene expression. Journal of Biological Chemistry 2004; 279: 51697"’703.
  40. Williams L, Bradley L, Smith A, Foxwell B. Signal transducer and activator of transcription 3 is the dominant mediator of the anti-inflammatory effects of IL-10 in human macrophages. The Journal of Immunology 2004; 172: 567"’76.
  41. Garcia R, Bowman TL, Niu G et al. Constitutive activation of Stat3 by the Src and JAK tyrosine kinases participates in growth regulation of human breast carcinoma cells. Oncogene 2001; 20: 2499"’513.
  42. Kisseleva T, Bhattacharya S, Braunstein J, Schindler CW. Signaling through the JAK/STAT pathway, recent advances and future challenges. Gene 2002; 285: 1–24.
  43. Masamune A, Satoh M, Kikuta K, Suzuki N, Shimosegawa T. Activation of JAK-STAT pathway is required for platelet-derived growth factor-induced proliferation of pancreatic stellate cells. World journal of gastroenterology 2005; 11: 3385"’91.
  44. Ziegler-Heitbrock L, Lotzerich M, Schaefer A et al. IFN-alpha induces the human IL-10 gene by recruiting both IFN regulatory factor 1 and Stat3. J Immunol 2003; 171: 285"’90.
  45. Asadullah K, Sterry K, Stephanek D. IL-10 is a key cytokine in psoriasis: proof of principle by IL-10 therapy: a new therapeutic approach. J Clin Invest 1998; 101: 783"’94.
  46. Hedrich CM, Rauen T, Apostolidis SA et al. Stat3 promotes IL-10 expression in lupus T cells through trans-activation and chromatin remodeling. Proceedings of the National Academy of Sciences 2014; 111: 13457"’62.
  47. Cheng F, Wang HW, Cuenca A et al. A critical role for Stat3 signaling in immune tolerance. Immunity 2003; 19: 425"’36.
  48. Hedrich CM, Bream JH. Cell type-specific regulation of IL-10 expression in inflammation and disease. Immunol Res 2010; 47: 185"’206.
  49. Liu BS, Cao Y, Huizinga TW, Hafler DA, Toes RE. TLR"mediated STAT3 and ERK activation controls IL"10 secretion by human B cells. European journal of immunology 2014; 44: 2121-9.
  50. Hossain DM, Panda AK, Manna A et al. FoxP3 acts as a cotranscription factor with STAT3 in tumor–induced regulatory T-cells. Immunity 2013; 39: 1057"’69.
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