Carbon monoxide-releasing molecule-A1 inhibits Th1/Th17 and stimulates Th2 differentiation in vitro.
Carbon monoxide (CO) is endogenously produced by haeme oxygenase-1 and has profound effects on intracellular signalling processes, generating anti-inflammatory, antiproliferative and antiapoptotic effects. A boron-containing compound CORM-A1 is capable of releasing CO in such a way to mimic physiological functions of haeme oxygenase-1. Considering the importance of Th1/Th17 versus Th2 balance in the final outcome of immune and inflammatory responses in this study we focused on immune-modulatory effects of CORM-A1 on murine lymph node-derived T cells in vitro and its influence on T-cell proliferation, activation and differentiation. Anti-CD3/CD28 antibody-triggered lymph node cells proliferation remained unaffected after 24-hour CORM-A1 treatment, as well as the expression of the early activation marker CD25. However, CORM-A1 successfully reduced the secretion of the two representative pro-inflammatory cytokines, IFN-γ and IL-17, while the secretion of anti-inflammatory cytokine IL-4 remained unchanged. Furthermore, CORM-A1 efficiently reduced the percentage of CD4(+) IFN-γ(+) and CD4(+) IL-17(+) cells, whereas CD4(+) IL-4(+) cell population increased after treatment. Also, CORM-A1 significantly reduced expression of transcription factor RORγT, necessary for Th17 development, but the expression of Th1-related and Th2-related transcription factors (T-bet and GATA-3, respectively) remained unchanged. In conclusion, our findings indicate that CO has anti-inflammatory role through the regulation of balance between pro-inflammatory Th1/Th17 and anti-inflammatory Th2 cells. Observed immunomodulatory effects of CORM-A1 could be useful for developing novel therapeutic approaches in managing Th1/Th17-mediated immune disorders.
Institute for Biological Research 'Sinisa Stankovic', University of Belgrade, Belgrade, Serbia.
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I
Nikolic
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M
Vujicic
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I
Stojanovic
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Stosic-Grujicic
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T
Saksida
D000818:Animals; D000906:Antibodies / Q000276:immunology; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D001880:Boranes / Q000494:pharmacology*; D018106:CD28 Antigens / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology; D002248:Carbon Monoxide / Q000494:pharmacology; D002254:Carbonates / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D050990:GATA3 Transcription Factor / Q000096:biosynthesis; D051547:Heme Oxygenase-1 / Q000378:metabolism; D007249:Inflammation / Q000276:immunology; D007371:Interferon-gamma / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000096:biosynthesis / Q000276:immunology; D015847:Interleukin-4 / Q000378:metabolism; D008198:Lymph Nodes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000096:biosynthesis; D020825:T-Box Domain Proteins / Q000096:biosynthesis; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology*; D058504:Th17 Cells / Q000187:drug effects / Q000276:immunology*; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology*; D000098815:T-bet Transcription Factor
D000906:Antibodies; D001880:Boranes; D018106:CD28 Antigens; D017252:CD3 Complex; D002254:Carbonates; D050990:GATA3 Transcription Factor; C494748:Gata3 protein, mouse; C508018:Il2ra protein, mouse; D020381:Interleukin-17; D053645:Interleukin-2 Receptor alpha Subunit; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; C503854:sodium boranocarbonate; D015847:Interleukin-4; D002248:Carbon Monoxide; D007371:Interferon-gamma; D051547:Heme Oxygenase-1