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Interleukin 6 stimulates macrophage MMP‐9 expression via COX‐2‐dependent induction of PGE2 synthesis and engagement of the EP4 receptor
Author(s) -
Falcone Domenick J,
Sakamoto Kazuko,
Steenport Michel L,
Khan KM Faisal,
Du Baoheng,
Dannenberg Andrew J
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.5.a193
Subject(s) - prostaglandin e2 receptor , receptor , chemistry , prostaglandin e2 , macrophage , matrix metalloproteinase , macrophage polarization , endocrinology , medicine , cancer research , biology , biochemistry , in vitro , agonist
Elevated levels of IL‐6 are associated with unstable atherosclerotic plaques. However, the pathophysiologic role of this inflammatory mediator in plaque destabilization remains unclear. In previous studies, we characterized a COX‐2‐PGE 2 ‐EP4 receptor axis that regulates macrophage MMP‐9 expression. In the current studies, we determined whether IL‐6 regulates macrophage proteinase expression via this axis. Results demonstrate that IL‐6 triggered a dose‐ and time‐dependent increase in COX‐2 antigen and mRNA levels in peritoneal and RAW264.7 macrophages. Activation of MAPK erk1/2 led to increased COX‐2 expression. The increase in COX‐2 was paralleled by rising PGE 2 levels, which was blocked by celecoxib, a COX‐2 inhibitor, or U0126, a MEK‐1 inhibitor. IL‐6 also induced the expression of microsomal PGE synthase‐1, an enzyme that converts PGH 2 to PGE 2 , and blocked expression of the degradative enzyme ‐ 15‐hydroxyprostaglandin‐dehydrogenase. Associated with the rise in PGE 2 levels was an increase in MMP‐9 expression, which was blocked by celecoxib, and the selective EP4 receptor antagonist ONO‐AE3208. Together, these data suggest a regulatory mechanism whereby IL‐6 induces macrophage MMP‐9 expression. Inhibition of IL‐6 induced MMP‐9 expression was achieved with COX‐2 inhibition or targeting the PGE 2 receptor EP4. These studies were supported by HL073375 and the Center for Cancer Prevention Research.