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Soluble tumor necrosis factor (TNF) receptor‐1 induces apoptosis via reverse TNF signaling and autocrine transforming growth factor‐β1
Author(s) -
Waetzig Georg H.,
Rosenstiel Philip,
Arlt Alexander,
Till Andreas,
Bräutigam Karen,
Schäfer Heiner,
RoseJohn Stefan,
Seegert Dirk,
Schreiber Stefan
Publication year - 2005
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.04-2073fje
Subject(s) - autocrine signalling , tumor necrosis factor alpha , cytokine , receptor , signal transduction , microbiology and biotechnology , apoptosis , transforming growth factor , biology , cancer research , immunology , biochemistry
The pro‐inflammatory cytokine tumor necrosis factor‐α (TNF‐α) plays a central role in inflammatory disorders. Transmembrane TNF‐α and its two receptors are cleaved by the proteinase TNF‐α converting enzyme (TACE), resulting in appreciable serum levels of soluble TNF‐α and soluble TNF‐α receptors (sTNFR1 and ‐2). The only known functions of sTNFR1 are to antagonize and buffer circulating TNF‐α. Here, we present evidence that sTNFR1 exerts immunoregulatory functions by induction of apoptosis in monocytes through reverse signaling via transmembrane TNF‐α. sTNFR1‐induced apoptosis is independent of death receptor pathways but depends on autocrine transforming growth factor (TGF)‐β1 signaling through the mitogen‐activated protein kinase p38α. This novel mechanism has implications for understanding the physiological role of sTNFR1 and for TNF‐α‐blocking therapies of autoimmune diseases.