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

Abstract

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 granulocyte 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-beta (TGF-beta), 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-beta, whereas lipopolysaccharide (LPS) + interferon-gamma-stimulated DC did not produce IL-12 in the presence of TGF-beta. 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.