Activin A Functions as a Th2 Cytokine in the Promotion of the Alternative Activation of Macrophages

Abstract

Activin A, a member of the TGF-β superfamily, is a pluripotent growth and differentiation factor. In this study, we report that murine Th cells produce activin A upon activation. Activin activity in the cultured CD4⁺ T cells was induced by anti-CD3 cross-linking. Activin βA mRNA level was increased in response to activation, indicating that activin production in CD4⁺ T cells is regulated at the mRNA level. Activin production was detected exclusively in CD4⁺CD25⁻ T cells, but not in CD4⁺CD25⁺ regulatory T cells. When CD4⁺ T cells were differentiated into Th cell subsets, higher activin secretion was detected when cultured under Th2-skewing conditions. The mRNA level of activin βA was abundant in Th2, but not in Th1 cells. Furthermore, secretion of activin was significantly higher in activated Th2 clones than in Th1 clones. The activin βA-proximal promoter contains a binding site for c-Maf, a Th2-specific transcriptional factor, at close proximity with an NF-AT binding site. c-Maf was able to synergize with NF-AT to transactivate activin βA gene, and both factors are implicated in activin βA transcription in Th2 cells. Activin A induced macrophages to express arginase-1 (M-2 phenotype), whereas it inhibited inducible NO synthase expression (M-1 phenotype) induced by IFN-γ. Taken together, these observations suggest that activin A is a novel Th2 cytokine that promotes differentiation of macrophages toward the M-2 phenotype.