title: MyD88-dependent production of IL-17F is modulated by the anaphylatoxin C5a via the Akt signaling pathway.
abstract: The interleukin-17 (IL-17) family of cytokines plays important roles in innate immune defenses against bacterial and fungal pathogens. While much is known about IL-17A, much less information is available about the IL-17F isoform. Here, we investigated gene expression and release of IL-17F and its regulation by the complement system. IL-17F was produced in mouse peritoneal elicited macrophages after TLR4 activation by LPS, peaking after 12 h. This effect was completely dependent on the presence of the adaptor protein MyD88. The copresence of the complement activation product, C5a (EC(50)=10 nM), amplified IL-17F production via the receptor C5aR. In vitro signaling studies indicated that LPS or C5a, or the combination, caused phosphorylation of Akt occurring at threonine 308 but not at serine 473. Treatment of macrophages with pharmacologic inhibitors of PI3K-Akt greatly reduced production of IL-17F as well as mRNA for IL-17F. In endotoxemia, C5a levels peaked at 6 h, while IL-17F levels peaked between 6-12 h. Full in vivo production of IL-17F during endotoxemia required C5a. A similar result was found in the cecal ligation and puncture sepsis model. These data suggest that maximal production of IL-17F requires complement activation and presence of C5a.
authors.affiliation: Department of Pathology, The University of Michigan Medical School, 1301 Catherine Rd., Ann Arbor, MI 48109-5602, USA.
authors.forename: Markus
authors.initials: M
authors.lastname: Bosmann
authors.forename: Vinay R
authors.initials: VR
authors.lastname: Patel
authors.forename: Norman F
authors.initials: NF
authors.lastname: Russkamp
authors.forename: Florence
authors.initials: F
authors.lastname: Pache
authors.forename: Firas S
authors.initials: FS
authors.lastname: Zetoune
authors.forename: J Vidya
authors.initials: JV
authors.lastname: Sarma
authors.forename: Peter A
authors.initials: PA
authors.lastname: Ward
mesh_terms: D000818:Animals; D003167:Complement Activation; D015936:Complement C5a / Q000378:metabolism*; D019446:Endotoxemia / Q000276:immunology / Q000378:metabolism; D007113:Immunity, Innate; D020381:Interleukin-17 / Q000096:biosynthesis* / Q000235:genetics; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000378:metabolism
chemical_list: C515932:Il17f protein, mouse; D020381:Interleukin-17; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D012333:RNA, Messenger; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D015936:Complement C5a; D051057:Proto-Oncogene Proteins c-akt