TNF Receptors Differentially Signal and Are Differentially Expressed and Regulated in the Human Heart

Abstract

Tumor necrosis factor (TNF) utilizes two receptors, TNFR1 and 2, to initiate target cell responses. We assessed expression of TNF, TNFRs and downstream kinases in cardiac allografts, and compared TNF responses in heart organ cultures from wild-type (WTC57BL/6), TNFR1-knockout (KO), TNFR2KO, TNFR1/2KO mice. In non-rejecting human heart TNFR1 was strongly expressed coincidentally with inactive apoptosis signal-regulating kinase-1 (ASK1) in cardiomyocytes (CM) and vascular endothelial cells (VEC). TNFR2 was expressed only in VEC. Low levels of TNF localized to microvessels. Rejecting cardiac allografts showed increased TNF in microvessels, diminished TNFR1, activation of ASK1, upregulated TNFR2 co-expressed with activated endothelial/epithelial tyrosine kinase (Etk), increased apoptosis and cell cycle entry in CM. Neither TNFR was expressed significantly by cardiac fibroblasts. In WTC57BL/6 myocardium, TNF activated both ASK1 and Etk, and increased both apoptosis and cell cycle entry. TNF-treated TNFR1KO myocardium showed little ASK1 activation and apoptosis but increased Etk activation and cell cycle entry, while TNFR2KO myocardium showed little Etk activation and cell cycle entry but increased ASK1 activation and apoptosis. These observations demonstrate independent regulation and differential functions of TNFRs in myocardium, consistent with TNFR1-mediated cell death and TNFR2-mediated repair.

RIPK3-Mediated Necroptosis Regulates Cardiac Allograft Rejection

“…TNFa could induce death through TNFR1 but promote proinflammatory responses through TNFR2 (51). Interestingly, myocardium in human donor heart grafts can modulate TNFR expression following rejection related injury by radically down-regulating TNFR1 and up-regulating TNFR2 surface expression following heart transplantation (6). Conversely, human and murine endothelial cells do not undergo radical changes in TNFR1 expression patterns before and after transplantation (6) and therefore are susceptible to TNFa-induced cell death.…”

“…Interestingly, myocardium in human donor heart grafts can modulate TNFR expression following rejection related injury by radically down-regulating TNFR1 and up-regulating TNFR2 surface expression following heart transplantation (6). Conversely, human and murine endothelial cells do not undergo radical changes in TNFR1 expression patterns before and after transplantation (6) and therefore are susceptible to TNFa-induced cell death. As the first barrier between graft and host, MVECs undergoing early necroptotic death after TNFa exposure may promote cardiac graft inflammation and subsequently augment rejection responses.…”

“…The death receptor pathway is induced by tumor necrosis factor receptor (TNFR) super-family members (TNFR1, Fas, TRAIL). TNF alpha (TNFa) can induce various cellular responses including programmed apoptosis and necroptosis through binding of TNFR1 (3,4) and has been shown to be an important contributor to heart graft rejection (5)(6)(7)(8)(9)(10). Interestingly, human and murine microvascular endothelial cells (MVECs) in heart grafts constitutively express TNFR1 before and after transplantation (5,6), suggesting that MVECs in donor grafts may be vulnerable to TNFamediated death.…”

“…TNF alpha (TNFa) can induce various cellular responses including programmed apoptosis and necroptosis through binding of TNFR1 (3,4) and has been shown to be an important contributor to heart graft rejection (5)(6)(7)(8)(9)(10). Interestingly, human and murine microvascular endothelial cells (MVECs) in heart grafts constitutively express TNFR1 before and after transplantation (5,6), suggesting that MVECs in donor grafts may be vulnerable to TNFamediated death. TNFa-induced necroptosis requires the formation of a complex of proteins called the necrosome, which include receptor interacting protein kinase 1 and 3 (RIPK1/3) following TNFR1 activation by TNFa (11)(12)(13).…”

TNFR2 expression on non-bone marrow-derived cells is crucial for lipopolysaccharide-induced septic shock and downregulation of soluble TNFR2 level in serum

“…[12][13][14][15] Interestingly, TNFR2 expression has also been reported on non-bone marrow (BM)-derived cells, such as vascular endothelial cells. 16 Non-BM TNFR2 expression can function through inhibiting collagen degradation and stimulating the proliferation of intestinal myofibroblasts. 17 Compared to TNFR1, the function of TNFR2 during inflammation and immune responses is poorly understood.…”