Expression and self-regulatory function of cardiac interleukin-6 during endotoxemia

Interleukin (IL)-6 reportedly has negative inotropic and hypertrophic effects on the heart. Here, we describe endotoxin-induced IL-6 in the heart that has not previously been well characterized. An intraperitoneal injection of a bacterial lipopolysaccharide into C57BL/6 mice induced IL-6 mRNA in the heart more strongly than in any other tissue examined. Induction of mRNA for two proinflammatory cytokines, IL-1β and tumor necrosis factor (TNF)-α, occurred rapidly before the induction of IL-6 mRNA and protein. Although stimulation of isolated rat neonatal myocardial cells with IL-1β or TNF-α induced IL-6 mRNA in vitro, nonmyocardial heart cells produced higher levels of IL-6 mRNA upon stimulation with IL-1β. In situ hybridization and immunohistochemical analyses localized the IL-6 expression primarily in nomnyocardial cells in vivo. Endotoxin-induced expression of cardiac IL-1β, TNF-α, and intercellular adhesion molecule I was augmented in IL-6-deficient mice compared with control mice. Thus cardiac IL-6, expressed mainly by nonmyocardial cells via IL-1β action during endotoxemia, is likely to suppress expression of proinfiammatory mediators and to regulate itself via a negative feedback mechanism.