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Complement dependency of cardiomyocyte release of mediators during sepsis
Author(s) -
Atefi Gelareh,
Zetoune Firas S.,
Herron Todd J.,
Jalife José,
Bosmann Markus,
AlAref Rami,
Sarma J. Vidya,
Ward Peter A.
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.11-183236
Subject(s) - dependency (uml) , complement (music) , sepsis , medicine , chemistry , computer science , biochemistry , phenotype , software engineering , complementation , gene
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.—Atefi, G., Zetoune, F. S., Herron, T. J., Jalife, J., Bosmann, M., Chen, A., Al‐Aref, R., Sarma, J. V., Ward, P. A. Complement dependency of cardiomyocyte release of mediators during sepsis. FASEB J. 25, 2500–2508 (2011). www.fasebj.org