title: Engagement of Fas on Macrophages Modulates Poly I:C induced cytokine production with specific enhancement of IP-10.
abstract: Viral double-stranded RNA (dsRNA) is recognised by pathogen recognition receptors such as Toll-Like Receptor 3 (TLR3) and retinoic acid inducible gene-I (RIG-I), and results in cytokine and interferon production. Fas, a well characterised death receptor, has recently been shown to play a role in the inflammatory response. In this study we investigated the role of Fas in the anti-viral immune response. Stimulation of Fas on macrophages did not induce significant cytokine production. However, activation of Fas modified the response of macrophages to the viral dsRNA analogue poly I:C. In particular, poly I:C-induced IP-10 production was significantly enhanced. A similar augmentation of IP-10 by Fas was observed following stimulation with both poly A:U and Sendai virus. Fas activation suppressed poly I:C-induced phosphorylation of the MAP kinases p38 and JNK, while overexpression of the Fas adaptor protein, Fas-associated protein with death domain (FADD), activated AP-1 and inhibited poly I:C-induced IP-10 production. Consistent with an inhibitory role for AP-1 in IP-10 production, mutation of the AP-1 binding site on the IP-10 promoter resulted in augmented poly I:C-induced IP-10. These results demonstrate that engagement of the Fas receptor plays a role in modifying the innate immune response to viral RNA.
authors: Department of Pathology, University College Cork, Cork, Ireland.
authors: Caitriona
authors: C
authors: Lyons
authors: Department of Medicine, University College Cork, Cork, Ireland.
authors: Philana
authors: P
authors: Fernandes
authors: Department of Medicine, University College Cork, Cork, Ireland.
authors: Liam J
authors: LJ
authors: Fanning
authors: Department of Medicine, University College Cork, Cork, Ireland; Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland.
authors: Aileen
authors: A
authors: Houston
authors: Department of Pathology, University College Cork, Cork, Ireland; Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland.
authors: Elizabeth
authors: E
authors: Brint
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D017209:Apoptosis; D015153:Blotting, Western; D049109:Cell Proliferation; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D053200:Fas-Associated Death Domain Protein / Q000235:genetics / Q000378:metabolism; D006801:Humans; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism* / Q000821:virology; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011070:Poly I-C / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D012367:RNA, Viral / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D010253:Respirovirus Infections / Q000188:drug therapy / Q000378:metabolism / Q000821:virology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D029082:Sendai virus / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects*; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism
chemical_list: D000998:Antiviral Agents; D016207:Cytokines; C505533:FADD protein, human; D053200:Fas-Associated Death Domain Protein; C508609:IL10 protein, human; D016328:NF-kappa B; D012333:RNA, Messenger; D012367:RNA, Viral; D018808:Transcription Factor AP-1; D016753:Interleukin-10; D011070:Poly I-C