Indecisive interleukin-4?

A study on page 1899 may explain the seemingly fickle ways of the cytokine interleukin (IL)-4. Yao and colleagues show how this quintessential T helper (Th) 2 cytokine can sometimes promote the opposite Th1 response. IL-4 is known as the key cytokine for polarizing naive T cells toward a Th2 phenotype, which is important for antibody production and protection against parasitic infections. Under some conditions, however, IL-4 has been shown to instead induce a Th1 response. Indeed, a recent study showed that mice treated with IL-4 during initial infection with Leishmania major had increased Th1 responses and were protected. If given later, IL-4 increased Th2 responses and exacerbated disease. Figure The prototypic Th2 cytokine IL-4 inhibits IL-10 production by DCs, thereby increasing the production of the Th1-promoting cytokine IL-12. Yao et al. now suggest that the regulation of another cytokine—IL-10—may explain these perplexing observations. They show that dendritic cells (DCs) stimulated in the presence of IL-4 made less IL-10 than those stimulated without IL-4. As a result, the IL-4–treated DCs produced more of the Th1-polarizing cytokine IL-12—known to be inhibited by IL-10—and polarized naive T cells toward a Th1 phenotype more effectively. IL-10 was critical for the increased Th1 response, as IL-4 did not increase IL-12 production or T cell polarization by IL-10–deficient DCs. IL-4 had the opposite effect on B cells, provoking increased IL-10 production. The authors suggest that the differential effect of IL-4 at different times during infection may reflect a switch from DCs to B cells as the predominant cell type that is presenting antigen.