TNF/IL-1-inducible protein TSG-6 potentiates plasmin inhibition by inter-alpha-inhibitor and exerts a strong anti-inflammatory effect in vivo.
TNF-stimulated gene 6 (tsg6), encoding a 35-kDa secretory glycoprotein (TSG-6), is induced in fibroblasts, chondrocytes, synovial cells, and mononuclear cells by the proinflammatory cytokines TNF-alpha and IL-1, or by LPS. Large amounts of TSG-6 protein were found in synovial fluids of patients with rheumatoid arthritis. TSG-6 protein forms a stable complex with components of the serine protease inhibitor, inter-alpha-inhibitor (I alpha I). In this work, we show that TSG-6 potentiates the inhibitory effect of l alpha l on the protease activity of plasmin. The plasmin/plasminogen activator system is important in the protease network associated with inflammation. To test the hypothesis that through their cooperative inhibitory effect on plasmin TSG-6 and l alpha l can modulate the protease network and thus inhibit inflammation, we examined the effect of TSG-6 on experimentally induced inflammation. Human recombinant TSG-6 protein showed a potent anti-inflammatory activity in the murine air pouch model of carrageenan- or IL-1-induced acute inflammation. The inhibitory effect of locally administered TSG-6 on the IL-1-induced cellular infiltration was comparable with that of systemic dexamethasone treatment. Two mutant TSG-6 proteins with single amino acid substitutions close to the N terminus showed a complete or partial loss of anti-inflammatory activity. The anti-inflammatory effect of the TNF/IL-1-inducible TSG-6 protein, along with its ability to inhibit protease action through interaction with l alpha l, suggests that TSG-6 production during inflammation is part of a negative feedback loop operating through the protease network.
Wisniewski
H G
HG
Department of Microbiology, Kaplan Cancer Center, New York University Medical Center, NY 10016, USA.
Hua
J C
JC
Poppers
D M
DM
Naime
D
D
Vilcek
J
J
Cronstein
B N
BN
D000510:Alpha-Globulins / Q000008:administration & dosage*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001483:Base Sequence; D002351:Carrageenan; D015815:Cell Adhesion Molecules / Q000008:administration & dosage*; D017931:DNA Primers / Q000737:chemistry; D004357:Drug Synergism; D005260:Female; D005341:Fibrinolysin / Q000037:antagonists & inhibitors*; D006801:Humans; D007249:Inflammation / Q000503:physiopathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D011994:Recombinant Proteins; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000510:Alpha-Globulins; D000893:Anti-Inflammatory Agents; D015815:Cell Adhesion Molecules; D017931:DNA Primers; D011994:Recombinant Proteins; D015842:Serine Proteinase Inhibitors; C072273:TNFAIP6 protein, human; C513057:Tnfaip6 protein, mouse; C011877:inter-alpha-inhibitor; D002351:Carrageenan; D005341:Fibrinolysin