A proposed role for Interleukin-6 in the modulation of Th2 asthmatic responses

Abstract

Abstract The incidence of allergic asthma in the United States and other industrialized countries has been increasing over the past few decades. One proposed explanation for this increase is the hygiene hypothesis, which states that a lack of early childhood exposure to high levels of environmental lipopolysaccharide (LPS) endotoxins from gram-negative bacteria increases the susceptibility to developing allergic diseases. Our lab has recently shown that LPS can indeed reduce Th2-driven, allergen-induced airway inflammation by inducing the up-regulation of the transcription factor T-bet in responding allergen-specific T cells, which we found was required to prevent the Th2 cell differentiation program. Studies have shown that like LPS, interleukin-6 (IL-6) reduces Th2 cell responses in asthma models. Due to these findings, our lab is now investigating the role of IL-6 in LPS-mediated Th2 cell suppression. In addition, some evidence suggests that IL-12 and IL-18 produced by dendritic cells are involved in the induction of T-bet by upregulating IFN-γ in T cells and other lymphoid cells. Here, we investigate the interplay of these cytokines in a house dust mite-induced asthma model in C57BL/6 (B6) mice. Through studies with IL-6 knock out and IL-6 receptor knock out B6 mice, we have shown that IL-6 modulates the expression of the IL-18 receptor on T cells, thus affecting the synergy of IL-18 and IL-12 to induce T-bet and prevent Th2 responses. We hypothesize that IL-6 affects T cell ability to respond to these cytokines by influencing the thresholds of IL-18 and IL-12 needed for T cell responses.