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1 Surgery, Indiana University, Indianapolis, Indiana, United States
2 Urology, Indiana Univ, Indianapolis, Indiana, United States
3 Physiology and Surgery, Indiana University, Indianapolis, Indiana, United States
* To whom correspondence should be addressed. E-mail: dmeldrum{at}iupui.edu.
Tumor Necrosis Factor-
(TNF) plays an important role in the development of heart failure. There is a direct correlation between myocardial function and myocardial TNF levels in humans. TNF may induce local inflammation to exert tissue injury. On the other hand, suppressor of cytokine signaling (SOCS) proteins have been shown to inhibit proinflammatory signaling. However, it is unknown whether TNF mediates myocardial inflammation via STAT3/SOCS3 signaling in the heart, and if so, whether this effect is through the type 1 55-kDa TNF receptor (TNFR1). We hypothesized that TNFR1 deficiency protects myocardial function and decreases myocardial interleukin (IL)-6 production via the STAT3/SOCS3 pathway in response to TNF. METHODS: Isolated male mouse hearts (n=4/group) from wild type (WT) and TNFR1 knockout (TNFR1KO) were subjected to direct TNF infusion (500 pg/ml/min x 30 min) while LVDP, +dP/dT, -dP/dT were continuously recorded. Heart tissue was analyzed for active forms of STAT3, p38, SOCS3 and SOCS1 (Western blot), as well as IL-1
and IL-6 (ELISA). Coronary effluent was analyzed for LDH activity. RESULTS: TNFR1KO had significantly better myocardial function, less myocardial LDH release and greater expression of SOCS3 (% of SOCS3/GAPDH: 45±4.5% vs. WT 22±6.5%) after TNF infusion. TNFR1 deficiency decreased STAT3 activation (% p-STAT3/STAT3: 29±6.4% vs. WT 45±8.8%). IL-6 was decreased in TNFR1KO (150.2±3.65 pg/mg protein) vs. WT (211.4±26.08). TNFR1 deficiency did not change expression of p38 and IL-1 following TNF infusion; however, it did alter SOCS3, IL-6 and TNF-induced cytotoxicity. These results suggest that deficiency of TNFR1 protects myocardium through SOCS3, and IL-6, but not p38 MAPK or IL-1.
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