title: C3a is required for the production of CXC chemokines by tubular epithelial cells after renal ishemia/reperfusion.
abstract: The complement system is one of the major ways by which the body detects injury to self cells, and the alternative pathway of complement is rapidly activated within the tubulointerstitium after renal ischemia/reperfusion (I/R). In the current study, we investigate the hypothesis that recognition of tubular injury by the complement system is a major mechanism by which the systemic inflammatory response is initiated. Gene array analysis of mouse kidney following I/R initially identified MIP-2 (CXCL2) and keratinocyte-derived chemokine (KC or CXCL1) as factors that are produced in a complement-dependent fashion. Using in situ hybridization, we next demonstrated that these factors are expressed in tubular epithelial cells of postischemic kidneys. Mouse proximal tubular epithelial cells (PTECs) in culture were then exposed to an intact alternative pathway and were found to rapidly produce both chemokines. Selective antagonism of the C3a receptor significantly attenuated production of MIP-2 and KC by PTECs, whereas C5a receptor antagonism and prevention of membrane attack complex (MAC) formation did not have a significant effect. Treatment of PTECs with an NF-kappaB inhibitor also prevented full expression of these factors in response to an intact alternative pathway. In summary, alternative pathway activation after renal I/R induces production of MIP-2 and KC by PTECs. This innate immune system thereby recognizes hypoxic injury and triggers a systemic inflammatory response through the generation of C3a and subsequent activation of the NF-kappaB system.
authors.affiliation: Department of Medicine, University of Colorado Health Sciences Center, Denver, CO 80262, USA. Joshua.Thurman@uchsc.edu
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Thurman
authors.forename: Amanda M
authors.initials: AM
authors.lastname: Lenderink
authors.forename: Pamela A
authors.initials: PA
authors.lastname: Royer
authors.forename: Kathrin E
authors.initials: KE
authors.lastname: Coleman
authors.forename: Jian
authors.initials: J
authors.lastname: Zhou
authors.forename: John D
authors.initials: JD
authors.lastname: Lambris
authors.forename: Raphael A
authors.initials: RA
authors.lastname: Nemenoff
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Quigg
authors.forename: V Michael
authors.initials: VM
authors.lastname: Holers
mesh_terms: D000818:Animals; D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; D018925:Chemokines / Q000235:genetics*; D019743:Chemokines, CXC / Q000096:biosynthesis* / Q000235:genetics; D003167:Complement Activation; D015926:Complement C3a / Q000235:genetics* / Q000502:physiology*; D004847:Epithelial Cells / Q000276:immunology* / Q000473:pathology; D020869:Gene Expression Profiling; D007249:Inflammation; D007674:Kidney Diseases; D007684:Kidney Tubules / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism*; D015427:Reperfusion Injury / Q000276:immunology* / Q000473:pathology
chemical_list: D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; D018925:Chemokines; D019743:Chemokines, CXC; C475895:Cxcl1 protein, mouse; C404915:Cxcl2 protein, mouse; D016328:NF-kappa B; D015926:Complement C3a