Effects of soluble TNF receptor treatment on lipopolysaccharide-induced myocardial cytokine expression

Tumor necrosis factor (TNF)-α plays a key role in the pathogenesis of septic shock syndrome, and myocardial TNF-α expression may contribute to this pathophysiology. We examined the myocardial expression of TNF-α-related cytokines and chemokines in mice exposed to lipopolysaccharide (LPS) and tested the effects of anti-TNF therapy on myocardial cytokine expression. Cytokine mRNA levels were measured by RNase protection assay, and protein levels in the plasma and myocardium were assessed by enzyme-linked immunosorbent assays. LPS (4 μg/g body wt ip) induced marked cytokine expression, including TNF-α, interleukin (IL)-1β, IL-6, and monocyte chemotactic protein (MCP)-1, in both the plasma and myocardium. Pretreatment with adenovirus-mediated TNF receptor fusion protein (AdTNFR1; 10⁹ plaque-forming units iv) decreased plasma cytokine levels. In contrast, whereas myocardial IL-1β expression was also suppressed, expression of IL-6 and MCP-1 was not inhibited by AdTNFR1. In summary, anti-TNF treatment differentially altered the cytokine expression in the plasma and myocardium during endotoxemia. Inability to block myocardial expression of IL-6 and MCP-1 suggests a possible mechanism for the failure of anti-TNF therapies in the treatment of endotoxin shock.