TSG-6: an IL-1/TNF-inducible protein with anti-inflammatory activity.
The pro-inflammatory cytokines IL-1 and TNF-alpha are primary mediators of the acute phase response, the complex reaction of the mammalian organism to infection and injury. Among the genes activated by TNF-alpha and IL-1 in a variety of cells is TNF-stimulated gene 6 (TSG-6). The TSG-6 cDNA encodes a secreted 35 kDa glycoprotein which is abundant in synovial fluids of patients with various forms of arthritis and detectable in serum of patients with different inflammatory or autoimmune disorders. TSG-6 protein consists of two structural domains: a hyaluronan-binding link module, the characteristic domain of the hyaladherin family of proteins, and a C-terminal CUB domain, present in a variety of diverse proteins. TSG-6 forms a stable complex with components of the plasma protein inter-alpha-inhibitor (I[alpha]I), a Kunitz-type serine protease inhibitor. TSG-6 and I(alpha)I synergize to inhibit plasmin, a serine protease involved in the activation of matrix metalloproteinases which are part of the proteolytic cascade associated with inflammation. Recombinant human TSG-6 protein exerts a potent anti-inflammatory effect in a murine model of acute inflammation. Modulation of the proteolytic network associated with inflammatory processes may be a mechanism whereby TSG-6, in cooperation with I(alpha)I, inhibits inflammation. Activation of the TSG-6 gene by pro-inflammatory cytokines, presence of TSG-6 protein in inflammatory lesions and its anti-inflammatory effect suggest a role for TSG-6 in a negative feed-back control of the inflammatory response.
Wisniewski
H G
HG
Department of Microbiology and the Kaplan Cancer Center, New York University Medical Center, NY 10016, USA.
Vilcek
J
J
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001665:Binding Sites; D015815:Cell Adhesion Molecules / Q000737:chemistry / Q000494:pharmacology* / Q000502:physiology*; D016207:Cytokines / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D006820:Hyaluronic Acid / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism; D007375:Interleukin-1 / Q000378:metabolism* / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism* / Q000494:pharmacology
D000893:Anti-Inflammatory Agents; D015815:Cell Adhesion Molecules; D016207:Cytokines; D007375:Interleukin-1; C072273:TNFAIP6 protein, human; D014409:Tumor Necrosis Factor-alpha; D006820:Hyaluronic Acid