Complement dependency of cardiomyocyte release of mediators during sepsis.
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Animals; Chemokine CCL3; Chemokine CXCL2; Chemokines; Complement C5a; Cytokines; Enzyme-Linked Immunosorbent Assay; Inflammation Mediators; Interleukin-17; Interleukin-6; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Myocytes, Cardiac; RNA, Messenger; Rats; Rats, Sprague-Dawley; Receptor, Anaphylatoxin C5a; Receptors, Chemokine; Receptors, Cytokine; Reverse Transcriptase Polymerase Chain Reaction; Sepsis; Tumor Necrosis Factor-alpha
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., Herron, T., Jalife, J., Bosmann, M., Al-Aref, R., Sarma, J., & Ward, P. (2011). Complement dependency of cardiomyocyte release of mediators during sepsis.. The FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 25 (7). http://dx.doi.org/10.1096/fj.11-183236