Dendritic cell maturation and IL‐12 synthesis induced by the synthetic immune‐response modifier S‐28463

Dendritic cells (DC) play a prominent role in the development of T cell‐immune responses to antigens and have a key influence over the differentiation of naive T cells into T helper cell type 1 (Th1) or Th2 effector cells. Consequently, there is considerable interest in pharmacological agents that might alter DC function and thereby modulate allergic inflammation. We examined the effects of the imidazoquinoline S‐28463 on human monocyte‐derived DC (Mo‐DC) cultured in granuloctye macrophage‐colony stimulating factor and interleukin (IL)‐4 to determine whether this agent might be useful in augmenting Th1 immunity. We determined that S‐28463 acts directly on Mo‐DC, inducing their maturation and enhancing their capacity to present antigen. Importantly, S‐28463 strongly induces synthesis of bioactive IL‐12 p70, a key Th1‐polarizing cytokine. We also examined the ability of S‐28463 to modulate DC function in the context of transforming growth factor‐β (TGF‐β), a negative, immunoregulatory cytokine released from the epithelium of nonlymphoid organs. S‐28463 was able to induce IL‐12 synthesis even in the presence of TGF‐β, whereas lipopolysaccharide (LPS) + interferon‐γ‐stimulated DC did not produce IL‐12 in the presence of TGF‐β. Taken together, our findings suggest that S‐28463 and LPS are exerting their effects via distinctly different pathways and indicate that S‐28463 may be beneficial in polarizing immune responses toward a Th1 response.