Activin A functions as a Th2 cytokine in the promotion of the alternative activation of macrophages

Activin A, a member of the TGF-beta 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 beta A 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 beta A 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 beta A-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 beta A gene, and both factors are implicated in activin beta A 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-gamma. Taken together, these observations suggest that activin A is a novel Th2 cytokine that promotes differentiation of macrophages toward the M-2 phenotype.