Author/Editor     Sodin-Šemrl, Snežna; Taddeo, Brunella; Tseng, Daniel; Varga, John; Fiore, Stefano
Title     Lipoxin A4 inhibits IL-1beta-induced IL-6, IL-8, and matrix metalloproteinase-3 production in human synovial fibriblasts and enhances synthesis of tissue inhibitors of metalloproteinases
Type     članek
Source     J Immunol
Vol. and No.     Letnik 164, št. 5
Publication year     2000
Volume     str. 2660-6
Language     eng
Abstract     Lipoxins are a novel class of endogenous eicosanoid mediators that potently inhibit inflammatory events by signaling via specific receptors expressed on phagocytic cells. Animal models have shown that lipoxin A4 (LXA4) down-regulates inflammation in vivo. Here we demonstrate, for the fast time, the expression of LXA4 receptors, and their up-regulation by IL-1beta, in normal human synovial fibroblasts (SF). We examined whether exogenous LXA4 abrogated IL-1beta stimulation of SF in vitro. IL-1beta induced the synthesis of 1L-6, IL-8, and matrix metalloproteinases (MMP)-1 and -3. At nanomolar concentrations, LXA4 inhibited these 1L-1beta responses with reduction of IL-6 and IL-8 synthesis, by 45 +- 7% and 75 +- 11%, respectively, and prevented IL-1beta-induced MMP-3 synthesis without significantly affecting MMP-1 levels. Furthermore, LXA4 induced a 2-fold increase of tissue inhibitor of metalloproteinase (TIMP)-1 and a -3-fold increase of TIMP-2 protein levels. LXA4, inhibitory responses were dose dependent and were abrogated by pretreatment with LXA4 receptor antiserum. LXA4-induced changes of IL-6 and TIMP were accompanied by parallel changes in mRNA levels. These results indicate that LXA4 in activated SF inhibits the synthesis of inflammatory cytokines and MMP and stimulates TIMP production in vitro. These findings suggest that LXA4 may be involved in a negative feedback loop opposing inflammatory cytokine-induced activation of SF.
Descriptors     FIBROBLASTS
HYDROXYEICOSATETRAENOIC ACIDS
INTERLEUKIN-1
INTERLEUKIN-6
STROMELYSIN 1
CELLS, CULTURED
IMMUNOSUPPRESSIVE AGENTS
INTERLEUKIN-8
RNA, MESSENGER
RECEPTORS, CELL SURFACE
SYNOVIAL MEMBRANE
METALLOPROTEINASES
UP-REGULATION (PHYSIOLOGY)