Soluble tumor necrosis factor (TNF) receptor-1 induces apoptosis via reverse TNF signaling and autocrine transforming growth factor-beta1.

Authors:
Georg H Waetzig, Philip Rosenstiel, Alexander Arlt, Andreas Till, Karen Bräutigam, Heiner Schäfer, Stefan Rose-John, Dirk Seegert, Stefan Schreiber
Year of publication:
2005
Volume:
19
Issue:
1
Issn:
0892-6638
Journal title abbreviated:
FASEB J
Journal title long:
FASEB journal
Impact factor:
5.299
Abstract: 
The pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) plays a central role in inflammatory disorders. Transmembrane TNF-alpha and its two receptors are cleaved by the proteinase TNF-alpha converting enzyme (TACE), resulting in appreciable serum levels of soluble TNF-alpha and soluble TNF-alpha receptors (sTNFR1 and -2). The only known functions of sTNFR1 are to antagonize and buffer circulating TNF-alpha. Here, we present evidence that sTNFR1 exerts immunoregulatory functions by induction of apoptosis in monocytes through reverse signaling via transmembrane TNF-alpha. sTNFR1-induced apoptosis is independent of death receptor pathways but depends on autocrine transforming growth factor (TGF)-beta1 signaling through the mitogen-activated protein kinase p38alpha. This novel mechanism has implications for understanding the physiological role of sTNFR1 and for TNF-alpha-blocking therapies of autoimmune diseases.