Suppression of inflammation in rat autoimmune myocarditis by S100A8/A9 through modulation of the proinflammatory cytokine network

• Published in: European journal of heart failure 2009-03, Vol.11 (3), p.229-237
• Main Authors: Otsuka, Kaoru, Terasaki, Fumio, Ikemoto, Masaki, Fujita, Shuichi, Tsukada, Bin, Katashima, Takashi, Kanzaki, Yumiko, Sohmiya, Koichi, Kono, Tatsuji, Toko, Haruhiro, Fujita, Masatoshi, Kitaura, Yasushi
• Format: Article
• Language: English
• Subjects: Animals; Autoimmune Diseases - drug therapy; Autoimmune Diseases - genetics; Autoimmune Diseases - metabolism; Autoimmune myocarditis; Calgranulin A - therapeutic use; Cytokines; Cytokines - biosynthesis; Cytokines - drug effects; Cytokines - genetics; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Experimental; Inflammation; Macrophages - metabolism; Male; Myocarditis - drug therapy; Myocarditis - genetics; Myocarditis - metabolism; Myocardium - metabolism; Rats; Rats, Inbred Lew; Recombinant Proteins; RNA, Messenger - biosynthesis; RNA, Messenger - genetics; S100A8/A9; Treatment Outcome
• ISSN: 1388-9842; 1879-0844
• DOI: 10.1093/eurjhf/hfn049

Aims S100A8/A9 is expressed in activated monocytes/macrophages and assumed to be heavily involved in the pathogenesis of acute inflammation. Although several studies have asserted that S100A8/A9 has a proinflammatory function, the exact biological function of S100A8/A9 is yet to be described. We examined the anti-inflammatory effects of S100A8/A9 on experimental autoimmune myocarditis (EAM) in rats. Methods and results Experimental autoimmune myocarditis was induced in Lewis rats by immunization with porcine cardiac myosin. The recombinant (R-) S100A8/A9 was injected intraperitoneally into EAM rats. R-S100A8/A9 attenuated the severity of myocarditis, as evidenced by echocardiographic and histological findings. In addition, we found that not only the mRNA expression of proinflammatory cytokines [interleukin (IL)-1β, IL-6, and tumour necrosis factor (TNF)-α] in the myocardium, but also their serum concentrations were suppressed in EAM rats treated with R-S100A8/A9. Nuclear factor-kappa B expression in inflammatory cells was also suppressed in the treated rats. To elucidate the mechanistic function of S100A8/A9 on proinflammatory cytokines in vivo, we used an ELISA on the supernatant of homogenized heart tissue treated with R-S100A8/A9. The findings revealed high-affinity binding of R-S100A8/A9 with IL-1β, IL-6, and TNF-α in the myocardium, suggesting the trapping of proinflammatory cytokines by R-S100A8/A9. Conclusion S100A8/A9 attenuates EAM through modulation of the proinflammatory cytokine network.