title: Mechanism of interleukin-10 inhibition of T-helper cell activation by superantigen at the level of the cell cycle.
abstract: We have analyzed the effects of interleukin-10 (IL-10) on the entry of quiescent CD4(+) T cells into the cell cycle upon stimulation with the superantigen staphylococcal enterotoxin B (SEB). IL-10 arrested cells at G0/G1. IL-10 treatment prevented the downregulation of p27(Kip1), an inhibitory protein that controls progression out of the G0 phase of the cell cycle. IL-10 also prevented the upregulation of the G1 cyclins D2 and D3, proteins necessary for entry and progression through the G1 phase of the cell cycle. Associated with the inhibition of the cell cycle, IL-10 suppressed SEB induction of interleukin-2 (IL-2). Addition of exogenous IL-2 to IL-10-treated cells significantly reversed the antiproliferative effects of IL-10. Moreover, IL-10 effects on the early G1 proteins p27(Kip1) and cyclin D2 were similarly reversed by exogenous IL-2. Although this reversal by IL-2 was pronounced, it was not complete, suggesting that IL-10 may have some effects not directly related to the suppression of IL-2 production. Cell separation experiments suggest that IL-10 can effect purified CD4(+) T cells directly, providing functional evidence for the presence of IL-10 receptors on CD4(+) T cells. IL-10 also inhibited expression of IL-2 transcriptional regulators c-fos and c-jun, which also inhibit other cell functions. Our studies show that the mechanism of IL-10 regulation of quiescent CD4(+) T-cell activation is mainly by blocking induction of IL-2 that is critical to downregulation of p27(Kip1) and upregulation of D cyclins in T-cell activation and entry into the cell cycle.
authors.affiliation: Department of Microbiology and Cell Science, University of Florida, Gainesville, FL 32611, USA. gperrin@micro.ifas.ufl.edu
authors.forename: G Q
authors.initials: GQ
authors.lastname: Perrin
authors.forename: H M
authors.initials: HM
authors.lastname: Johnson
authors.forename: P S
authors.initials: PS
authors.lastname: Subramaniam
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D002453:Cell Cycle / Q000276:immunology*; D018797:Cell Cycle Proteins; D002455:Cell Division / Q000276:immunology; D056742:Cyclin D2; D056743:Cyclin D3; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors; D016213:Cyclins / Q000378:metabolism; D004768:Enterotoxins / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000276:immunology; D006131:Growth Inhibitors / Q000494:pharmacology; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D016753:Interleukin-10 / Q000037:antagonists & inhibitors / Q000502:physiology*; D007376:Interleukin-2 / Q000037:antagonists & inhibitors / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000166:cytology; D008213:Lymphocyte Activation / Q000276:immunology; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D018089:Superantigens / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology / Q000201:enzymology / Q000276:immunology*; D025521:Tumor Suppressor Proteins; D015854:Up-Regulation / Q000276:immunology
chemical_list: C080336:CCND2 protein, human; C534696:CCND3 protein, human; D018797:Cell Cycle Proteins; D056742:Cyclin D2; D056743:Cyclin D3; D016213:Cyclins; D004768:Enterotoxins; D006131:Growth Inhibitors; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D008869:Microtubule-Associated Proteins; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D018089:Superantigens; D025521:Tumor Suppressor Proteins; D016753:Interleukin-10; D050760:Cyclin-Dependent Kinase Inhibitor p27; C031818:enterotoxin B, staphylococcal; D018844:Cyclin-Dependent Kinases