Differential regulation of myocardial NF kappa B following acute or chronic TNF-alpha exposure

Tumor necrosis factor alpha (TNF-alpha) is a critical mediator of myocardia l dysfunction during acute inflammatory states. TNF-alpha is also present i n the serum of patients with chronic cardiac diseases. In monocytes, TNF-al pha stimulates cells by activating distinct signaling pathways that involve nuclear translocation of NF-kappaB. Since NF kappaB may also regulate the expression of genes that could contribute to myocardial dysfunction, the ca rdiomyocyte NF kappaB activation following acute or chronic TNF-alpha chall enges was investigated. To accomplish this, the authors either acutely admi nistered TNF-alpha. to healthy mice, or used transgenic mice which chronica lly overexpress TNF-alpha exclusively in cardiac myocytes. Following acute administration of TNF-alpha, cardiac NF kappaB translocation was detected f rom 15 min to 2 h post-challenge. The time course of I kappaB alpha degrada tion was consistent with the kinetics of NF kappaB translocation. I kappaB beta degradation was slower and less dramatic. In transgenic mice chronical ly overexpressing TNF-alpha, myocardial NF kappaB activation was detected a t all ages tested (21, 40, and 75 days). In contrast to acutely challenged animals, two distinct NF kappaB proteins were activated in chronically chal lenged animals, p50-p65 heterodimers as well as p50 homodimers. Activation of both could be transiently blocked by administration of a recombinant chi meric TNF-alpha receptor antagonist (rhTNTR:Fc). I kappaB alpha, but not I kappaB beta, levels were elevated in transgenics when compared to wild-type animals. These data indicate that following acute TNF-alpha administration , which simulates bacterial sepsis, myocardial p50-p65 translocates within minutes. Chronic TNF-alpha exposure, which is thought to occur in long-stan ding congestive heart failure, results in translocation of transcriptionall y inactive p50 homodimers in addition to transcription ally active p50-p65 heterodimers. It is speculated that activation of p50 homodimers constitute s an adaptive response to minimize the inflammatory consequences of chronic cardiac TNT-alpha exposure. (C) 2001 Academic Press.