title: Complement dependency of cardiomyocyte release of mediators during sepsis.
abstract: We have recently shown that antibody-induced blockade of C5a, C5a receptors, or IL-17A greatly reduced the harmful outcomes of sepsis. In the current study, normal cardiomyocytes from young (300 g) male Sprague-Dawley rats responded in vitro to C5a (ED(50)=55 nM) with release of IL-6 and TNFα, peaking between 2 to 8 h. Neutralizing antibodies to mouse C5a or IL-17A (ED(50)=40 μg for each, based on improved survival) reduced spontaneous in vitro release of cardiosuppressive cytokines and chemokines in cardiomyocytes obtained from mice with polymicrobial sepsis. A non-neutralizing C5a antibody had no such effects. Cardiomyocytes from septic mice (C57Bl/6) showed increased mRNA for TNFR1, IL-6 (gp80), and C5aR at 6 h after sepsis. Cardiomyocytes from septic C5aR(-/-) or C5L2(-/-) mice did not show spontaneous in vitro release of cytokines and chemokines. These data suggest that cardiomyocytes from septic mice release suppressive cytokines in a C5a-, C5aR-, and IL-17A-dependent manner, followed by mediator reactivity with receptors on cardiomyocytes, resulting in defective contractility and relaxation. These data may be relevant to a strategy for the treatment of heart dysfunction developing during sepsis.
authors.affiliation: The University of Michigan Medical School, Department of Pathology, 1301 Catherine Rd. Box 5602, Ann Arbor, MI 48109-5602, USA.
authors.forename: Gelareh
authors.initials: G
authors.lastname: Atefi
authors.forename: Firas S
authors.initials: FS
authors.lastname: Zetoune
authors.forename: Todd J
authors.initials: TJ
authors.lastname: Herron
authors.forename: José
authors.initials: J
authors.lastname: Jalife
authors.forename: Markus
authors.initials: M
authors.lastname: Bosmann
authors.forename: Rami
authors.initials: R
authors.lastname: Al-Aref
authors.forename: J Vidya
authors.initials: JV
authors.lastname: Sarma
authors.forename: Peter A
authors.initials: PA
authors.lastname: Ward
mesh_terms: D000818:Animals; D054405:Chemokine CCL3 / Q000097:blood / Q000378:metabolism; D054426:Chemokine CXCL2 / Q000097:blood / Q000378:metabolism; D018925:Chemokines / Q000097:blood / Q000378:metabolism; D015936:Complement C5a / Q000378:metabolism*; D016207:Cytokines / Q000097:blood / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D018836:Inflammation Mediators / Q000097:blood / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism; D015850:Interleukin-6 / Q000097:blood / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044087:Receptor, Anaphylatoxin C5a / Q000235:genetics / Q000378:metabolism; D019707:Receptors, Chemokine / Q000235:genetics / Q000378:metabolism; D018121:Receptors, Cytokine / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018805:Sepsis / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000097:blood / Q000378:metabolism
chemical_list: C000594938:C5ar2 protein, mouse; D054405:Chemokine CCL3; D054426:Chemokine CXCL2; D018925:Chemokines; D016207:Cytokines; D018836:Inflammation Mediators; D020381:Interleukin-17; D015850:Interleukin-6; D012333:RNA, Messenger; D044087:Receptor, Anaphylatoxin C5a; D019707:Receptors, Chemokine; D018121:Receptors, Cytokine; D014409:Tumor Necrosis Factor-alpha; D015936:Complement C5a