Tumor necrosis factor receptors have divergent effects on NF‐kB activation in cardiac progenitor cells

Background Despite abundant endogenous cardiac progenitor cells (CPCs) the reparative capacity of heart is insufficient to normalize structural and functional deteriorations in response to myocardial injury. Failing hearts exhibit an augmented pro‐inflammatory response. We evaluated tumor necrosis factor‐α (TNF) receptor (TNFR) signaling and its effect on activation of downstream mediator NF‐κB in CPCs. Methods/Results CPCs (c‐kit + /lin − ) isolated from wild type (WT), TNFR1 and TNFR2 knockout (−/ −) mouse hearts were treated with TNF (20 ng/mL) for various time periods. Total RNA, protein and cytosolic and nuclear extracts were evaluated for the expression of TNFR1, TNFR2, NF‐κB subunits p65 and p50 and MAPK signaling. NF‐κB activation was evaluated by gel‐shift assays. The results indicated that CPCs have a functional TNFR‐signaling axis with constitutive expression of TNFR1, and a stress‐induced TNFR2 expression. WT and TNFR2−/ − CPCs exhibited equivalent TNF‐induced NF‐κB activation. However, TNF‐induced NF‐κB activation was abolished in TNFR1−/ − CPCs. These divergent effects on NF‐κB activation in TNFR1 and R2 −/ − CPCs were also reflected in differential activation of p38 and JNK MAPK activation in response to TNF stimulation. Conclusions TNFR1 and TNFR2 in CPCs induce divergent effects on NF‐κB and MAPK activation and may play important roles in CPC function after myocardial injury. Financial support: NIH, AHA.