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Lipopolysaccharide induction of monocyte matrix metalloproteinases is regulated by the tyrosine phosphorylation of cytosolic phospholipase A 2
Author(s) -
Shankavaram Uma T.,
DeWitt David L.,
Wahl Larry M.
Publication year - 1998
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1002/jlb.64.2.221
Subject(s) - phospholipase a2 , tyrosine phosphorylation , matrix metalloproteinase , phosphorylation , signal transduction , biology , tyrosine , monocyte , arachidonic acid , microbiology and biotechnology , lipopolysaccharide , cancer research , biochemistry , endocrinology , immunology , enzyme
Activation of human monocytes with lipopolysaccharide (LPS) results in the production of matrix metalloproteinases (MMPs) through a prostaglandin E 2 (PGE 2 )‐cAMP‐dependent pathway. In this study, the early signaling events involved in this signal transduction pathway were evaluated. Pretreatment of human peripheral blood monocytes with herbimycin A, a tyrosine kinase inhibitor, or arachidonyl trifluoromethyl ketone (AACOCF 3 ), a specific inhibitor of cytosolic phospholipase A 2 (cPLA 2 ) inhibited the induction of PGE 2 by LPS. This resulted in the inhibition of protein expression of gelatinase B (MMP‐9) and interstitial collagenase (MMP‐1), two major MMPs secreted by activated monocytes. Addition of arachidonic acid (AA) reversed the inhibitory effect of herbimycin A or AACOCF 3 on monocyte MMP production, indicating the importance of tyrosine phosphorylation and the involvement of cPLA 2 at an early stage in the signal transduction pathway of MMPs. This finding was further supported by LPS‐induced shift in cPLA 2 migration and tyrosine phosphorylation based on immunoblotting and immunoprecipitation studies. These results provide evidence that tyrosine phosphorylation of cPLA 2 is one of the initial steps needed for the LPS induced MMP production in human monocytes. J. Leukoc. Biol . 64: 221–227; 1998.