title: The interaction between C5a and both C5aR and C5L2 receptors is required for production of G-CSF during acute inflammation.
abstract: The complement activation product, C5a, is a key factor for regulation of inflammatory responses. C5a and C5adesArg bind to their receptors, C5aR and C5L2, but the functional roles of C5L2 remain controversial. We screened the patterns of 23 inflammatory mediators in cultures of LPS-activated mouse peritoneal elicited macrophages (PEMs) in the presence or absence of recombinant mouse C5a. Production of most mediators studied was suppressed by C5a, whereas G-CSF production was enhanced. G-CSF gene expression and secretion from PEMs was amplified two- to threefold by C5a in a dose- and time-dependent fashion. The degradation product C5adesArg promoted lower levels of G-CSF. The effects of C5a on G-CSF were associated with activation of PI3K/Akt and MEK1/2 signaling pathways. C5a did not enhance G-CSF production in cultures of PEMs from either C5aR- or C5L2-deficient mice, indicating that both C5a receptors are indispensable for mediating the effects of C5a in the production of G-CSF. Finally, G-CSF levels in plasma during polymicrobial sepsis after cecal ligation and puncture were substantially lower in C5aR- or C5L2-deficient mice as compared with that in C57BL/6J WT mice. These findings elucidate the functional characteristics of the C5L2 receptor during the acute inflammatory response.
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109-5602, USA.
authors.forename: Markus
authors.initials: M
authors.lastname: Bosmann
authors.forename: Mikel D
authors.initials: MD
authors.lastname: Haggadone
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: D000208:Acute Disease; D000818:Animals; D015936:Complement C5a / Q000276:immunology* / Q000378:metabolism; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D016179:Granulocyte Colony-Stimulating Factor / Q000096:biosynthesis* / Q000276:immunology; D007249:Inflammation / Q000276:immunology* / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D060888:Real-Time Polymerase Chain Reaction; D044087:Receptor, Anaphylatoxin C5a; D019707:Receptors, Chemokine / Q000276:immunology* / Q000378:metabolism; D011951:Receptors, Complement / Q000276:immunology* / Q000378:metabolism; D018805:Sepsis / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology
chemical_list: C488033:C5AR1 protein, human; C417003:C5aR2 protein, human; D044087:Receptor, Anaphylatoxin C5a; D019707:Receptors, Chemokine; D011951:Receptors, Complement; D016179:Granulocyte Colony-Stimulating Factor; D015936:Complement C5a
keywords: Akt; Cecal ligation and puncture; MEK1/2; Macrophages; Sepsis