The dsRNA-mimetic poly (I:C) and IL-18 synergize for IFNgamma and TNFalpha expression.
Interleukin (IL)-18 bioactivity and dsRNA sensing by receptors of innate immunity are key components of anti-viral host defense. Despite extensive data on signal transduction activated by both pathways knowledge on cross-communication is incomplete. By using human PBMC and predendritic KG1 cells, as prototypic IL-18-responsive cellular models, we sought to assess cytokine production under the influence of IL-18 and the dsRNA-mimetic poly (I:C). Here, we report on potent synergy between both mediators concerning pro-inflammatory IFNgamma and TNFalpha production. KG1 data revealed that synergistic induction likely relied on TLR3 and was associated with prolonged/increased activation of NF-kappaB, as detected by IkappaB analysis and luciferase reporter assays, respectively. Moreover, extended activation of JNK was mediated by IL-18/poly (I:C). Although vital for innate immunity, overwhelming induction of inflammatory cytokines during viral infections poses the threat of serious collateral tissue damage. The stunning synergism inherent to IL-18/dsRNA-induced TNFalpha/IFNgamma detected herein may contribute to this pathological phenomenon.
Balah
Amany
A
Pharmazentrum Frankfurt/ZAFES, University Hospital Goethe-University, Theodor-Stern-Kai 7, Frankfurt am Main, Germany.
Akool
El-Sayed
el-S
Bachmann
Malte
M
Pfeilschifter
Josef
J
Mühl
Heiko
H
D040761:Biomimetic Materials / Q000494:pharmacology; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology; D006801:Humans; D007239:Infections / Q000276:immunology / Q000821:virology*; D007371:Interferon-gamma / Q000096:biosynthesis*; D020382:Interleukin-18 / Q000276:immunology* / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology; D011070:Poly I-C / Q000276:immunology* / Q000494:pharmacology; D012330:RNA, Double-Stranded / Q000276:immunology*; D051196:Toll-Like Receptor 3 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
D020382:Interleukin-18; D012330:RNA, Double-Stranded; C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D011070:Poly I-C