Tumor necrosis factor-alpha (TNF-alpha) is a potent proinflammatory cytokine produced predominantly by activated macrophages, and plays a central role in the protective immunity against intracellular pathogens and the pathogenesis of autoimmune and inflammatory diseases. While both the soluble and transmembrane forms of TNF-alpha (sTNF-alpha and tmTNF-alpha) are biologically functional, the latter but not the former acts as a receptor besides as a ligand, and transmit a retrograde signal in a cell-to-cell contact manner. The production of TNF-alpha by macrophages under Th2-type (allergic) inflammatory conditions has been ill defined, compared to that under Th1-type inflammatory conditions. Here we examined the effect of representative Th2-inducing cytokines IL-4 and IL-33 on the TNF-alpha expression in macrophages. IL-4 induced the production of neither sTNF-alpha nor tmTNF-alpha while IL-33 promoted the production of sTNF-alpha with no detectable tmTNF-alpha. Notably, the combination of IL-4 and IL-33 elicited the tmTNF-alpha expression on macrophages, in addition to the enhanced production of sTNF-alpha and IL-6. The IL-4/IL-33-elicited tmTNF-alpha expression was not observed in IL-6-deficient macrophages, suggesting the involvement of macrophage-derived IL-6 in the tmTNF-alpha expression. Indeed, the stimulation of macrophages with the combination of IL-4 and IL-6 induced the tmTNF-alpha expression with no detectable production of sTNF-alpha. Thus, IL-4 and IL-33 synergistically elicit the tmTNF-alpha expression on macrophages through the autocrine action of IL-6. (C) 2012 Elsevier Inc. All rights reserved.