title: Th2-inducing cytokines IL-4 and IL-33 synergistically elicit the expression of transmembrane TNF-α on macrophages through the autocrine action of IL-6.
abstract: Tumor necrosis factor-α (TNF-α) 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-α (sTNF-α and tmTNF-α) 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-α 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-α expression in macrophages. IL-4 induced the production of neither sTNF-α nor tmTNF-α while IL-33 promoted the production of sTNF-α with no detectable tmTNF-α. Notably, the combination of IL-4 and IL-33 elicited the tmTNF-α expression on macrophages, in addition to the enhanced production of sTNF-α and IL-6. The IL-4/IL-33-elicited tmTNF-α expression was not observed in IL-6-deficient macrophages, suggesting the involvement of macrophage-derived IL-6 in the tmTNF-α expression. Indeed, the stimulation of macrophages with the combination of IL-4 and IL-6 induced the tmTNF-α expression with no detectable production of sTNF-α. Thus, IL-4 and IL-33 synergistically elicit the tmTNF-α expression on macrophages through the autocrine action of IL-6.
authors.affiliation: Department of Immune Regulation, Tokyo Medical and Dental University Graduate School, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Ogawa
authors.forename: Kaori
authors.initials: K
authors.lastname: Mukai
authors.forename: Yohei
authors.initials: Y
authors.lastname: Kawano
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Minegishi
authors.forename: Hajime
authors.initials: H
authors.lastname: Karasuyama
mesh_terms: D000818:Animals; D019898:Autocrine Communication; D002462:Cell Membrane / Q000276:immunology; D000067596:Interleukin-33; D015847:Interleukin-4 / Q000494:pharmacology / Q000502:physiology*; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D007378:Interleukins / Q000494:pharmacology / Q000502:physiology*; D008264:Macrophages / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018418:Th2 Cells / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
chemical_list: C506535:Il33 protein, mouse; D000067596:Interleukin-33; D015850:Interleukin-6; D007378:Interleukins; D014409:Tumor Necrosis Factor-alpha; D015847:Interleukin-4