title: Expression of constitutively active STAT3 can replicate the cytokine-suppressive activity of interleukin-10 in human primary macrophages.
abstract: There is general agreement that signal transducer and activation of transcription 3 (STAT3) is required to mediate the anti-inflammatory activities of interleukin (IL)-10. However, STAT3 is activated by multiple factors that do not share the anti-inflammatory activity of IL-10. The question remains whether STAT3 is sufficient for the anti-inflammatory effects or whether there are other signals required, as had been suggested previously. We set out to map the human IL-10 receptor and to identify the key elements involved in transducing the cytokine-suppressive effects of IL-10. We were able to show an absolute requirement for both of the tyrosine residues found within the YXXQ-STAT3-docking site within the IL-10 receptor 1 and that no other signals appeared to be required. We used a constitutively active STAT3 to determine whether expression of this factor could suppress lipopolysaccharide-induced tumor necrosis factor and IL-6 production. Our data show that STAT3 activity can suppress both IL-6 and tumor necrosis factor production in lipopolysaccharide-stimulated macrophages. However, in synovial fibroblasts, STAT3 did not suppress IL-6 production, suggesting that the cellular environment plays an important role in dictating whether STAT3 drives a pro- or anti-inflammatory response.
authors.affiliation: Kennedy Institute of Rheumatology Division, Imperial College London, ARC Building, 1 Aspenlea Road, London W6 8LH, United Kingdom. b.foxwell@imperial.ac.uk
authors.forename: Lynn M
authors.initials: LM
authors.lastname: Williams
authors.forename: Usha
authors.initials: U
authors.lastname: Sarma
authors.forename: Kate
authors.initials: K
authors.lastname: Willets
authors.forename: Tim
authors.initials: T
authors.lastname: Smallie
authors.forename: Fionula
authors.initials: F
authors.lastname: Brennan
authors.forename: Brian M J
authors.initials: BM
authors.lastname: Foxwell
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D006801:Humans; D016753:Interleukin-10 / Q000494:pharmacology*; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D012333:RNA, Messenger / Q000032:analysis; D053701:Receptors, Interleukin-10 / Q000502:physiology; D050796:STAT3 Transcription Factor / Q000502:physiology*; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D000093242:Interleukin-6 Inhibitors
chemical_list: D016753:Interleukin-10; D015850:Interleukin-6; D008070:Lipopolysaccharides; D020928:Mitogen-Activated Protein Kinases; D016328:NF-kappa B; D012333:RNA, Messenger; D053701:Receptors, Interleukin-10; D050796:STAT3 Transcription Factor; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014409:Tumor Necrosis Factor-alpha; D000093242:Interleukin-6 Inhibitors; C106644:SOCS3 protein, human