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Articles in PresS, published online ahead of print May 22, 2002
Am J Physiol Cell Physiol, 10.1152/ajpcell.00609.2001
Submitted on December 20, 2001
Accepted on May 15, 2002
1 Pharmacology and Toxicology, Rutgers University, Piscataway, New Jersey, USA
2 Environmental and Community Medicine, UMDNJ-Robert Wood Johnson Medical School, Piscataway, New Jersey, USA
* To whom correspondence should be addressed. E-mail: jlaskin{at}eohsi.rutgers.edu.
HSP60, an endogenous ligand for the toll-like 4 receptor, is generated in response to inflammation, tissue injury and/or stress and stimulates macrophages to produce cytotoxic and proinflammatory mediators including nitric oxide, TNF-
, IL-6 and IL-12. In the present studies we report that HSP60 is an effective inducer of cyclooxygenase-2 (COX-2) in macrophages, as well as endothelial cells. In both cell types, the synthesis of COX-2 was coordinate with induction of nitric oxide synthase (NOS2), and nitric oxide production. Using promoter constructs in transient transfection assays, optimal expression of COX-2 in macrophages was found to require NF-
B, the cAMP response element (CRE), and nuclear factor (NF)-IL6, but not the E-Box. Mobility shift assays revealed that HSP60 induced NF-B and CRE binding activity, while C/EBP, which binds to NF-IL-6, was constitutively active in the cells. Both c-JUN and CREB bound to the CRE, while C/EBPb bound to NF-IL-6. These data indicate that NFB, C/EBPß, c-JUN and CREB are important in HSP60-induced expression of COX-2. The c-JUN-N-terminal kinase (JNK), p44/42 MAP kinase (ERK1/2) and p38 MAP kinase were rapidly activated by HSP60 in the macrophages. PD98059, an inhibitor of phosphorylation of ERK1/2, caused a marked inhibition of HSP60-induced COX-2 and NOS2 expression. Unexpectedly, SB203580, a selective inhibitor of p38 kinase, inhibited HSP60-induced expression of COX-2, but not NOS2. These data indicate that MAP kinase signaling plays distinct roles in regulating HSP60-induced expression of COX-2 and NOS2.
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