Soluble tumor necrosis factor (TNF) receptor-1 induces apoptosis via reverse TNF signaling and autocrine transforming growth factor-beta1.
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.
Waetzig
Georg H
GH
Institute of Clinical Molecular Biology, Schleswig-Holstein University Medical Center, Kiel, Germany.
Rosenstiel
Philip
P
Arlt
Alexander
A
Till
Andreas
A
Bräutigam
Karen
K
Schäfer
Heiner
H
Rose-John
Stefan
S
Seegert
Dirk
D
Schreiber
Stefan
S
D051722:ADAM Proteins; D000072198:ADAM17 Protein; D000328:Adult; D017209:Apoptosis / Q000502:physiology*; D002460:Cell Line; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000502:physiology; D005260:Female; D006801:Humans; D008666:Metalloendopeptidases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009000:Monocytes / Q000166:cytology / Q000201:enzymology / Q000378:metabolism / Q000502:physiology; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism* / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D012995:Solubility; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D047888:Receptors, Tumor Necrosis Factor, Type I; C508960:TGFB1 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; D020928:Mitogen-Activated Protein Kinases; D051722:ADAM Proteins; D008666:Metalloendopeptidases; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human