Differential Regulation of Myocardial NF κ B Following Acute or Chronic TNF- α Exposure

Tumor necrosis factor α (TNF- α) is a critical mediator of myocardial dysfunction during acute inflammatory states. TNF- α is also present in the serum of patients with chronic cardiac diseases. In monocytes, TNF- α stimulates cells by activating distinct signaling pathways that involve nuclear translocation of NF κ B. Since NF κ B may also regulate the expression of genes that could contribute to myocardial dysfunction, the cardiomyocyte NF κ B activation following acute or chronic TNF- α challenges was investigated. To accomplish this, the authors either acutely administered TNF- α to healthy mice, or used transgenic mice which chronically overexpress TNF- α exclusively in cardiac myocytes. Following acute administration of TNF- α, cardiac NF κ B translocation was detected from 15 min to 2 h post-challenge. The time course of I κ B α degradation was consistent with the kinetics of NF κ B translocation. Iκ B β degradation was slower and less dramatic. In transgenic mice chronically overexpressing TNF-α , myocardial NF κ B activation was detected at all ages tested (21, 40, and 75 days). In contrast to acutely challenged animals, two distinct NF κ B proteins were activated in chronically challenged animals, p50–p65 heterodimers as well as p50 homodimers. Activation of both could be transiently blocked by administration of a recombinant chimeric TNF- α receptor antagonist (rhTNFR:Fc). I κ B α, but not Iκ B β, levels were elevated in transgenics when compared to wild-type animals. These data indicate that following acute TNF- α administration, which simulates bacterial sepsis, myocardial p50–p65 translocates within minutes. Chronic TNF- α exposure, which is thought to occur in long-standing congestive heart failure, results in translocation of transcriptionally inactive p50 homodimers in addition to transcriptionally active p50–p65 heterodimers. It is speculated that activation of p50 homodimers constitutes an adaptive response to minimize the inflammatory consequences of chronic cardiac TNF- α exposure.