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1 Department of Pharmacology and Toxicology, Rutgers University and 2 Department of Environmental and Community Medicine, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, Piscataway, New Jersey 08854
The 60-kDa heat shock protein (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, tumor necrosis factor (TNF)-
, interleukin
(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 (NOS)-2 and
with nitric oxide production. With the use of promoter constructs in
transient transfection assays, optimal expression of COX-2 in
macrophages was found to require nuclear factor (NF)-
B, the
cAMP-response element (CRE), and NF-IL-6, but not the E-box. Mobility
shift assays revealed that HSP60 induced NF-B and CRE binding
activity, while CCAAT/enhancer binding protein (C/EBP), which
binds to NF-IL-6, was constitutively active in the cells. Both c-Jun
and CRE binding protein (CREB) bound to the CRE, while
C/EBP-
bound to NF-IL-6. These data indicate that NF-B,
C/EBP-, c-Jun, and CREB are important in HSP60-induced expression of
COX-2. The c-Jun-NH2-terminal kinase (JNK), p44/42
mitogen-activated protein (MAP) kinase [extracellular signal-regulated
kinase 1/2 (ERK1/2)], and p38 MAP kinase were rapidly activated
by HSP60 in the macrophages. PD-98059, an inhibitor of
phosphorylation of ERK1/2, caused a marked inhibition of
HSP60-induced COX-2 and NOS-2 expression. Unexpectedly,
SB-203580, a p38 kinase antagonist, was found to block HSP60-induced
expression of COX-2, but not NOS-2. These data indicate that both
ERK1/2 kinase and p38 kinase play a role in regulating HSP60-induced
expression of COX-2.
nitric oxide; inflammation; cytokines; monocytes/macrophages
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