Expression of the chemokine (C-C motif) ligand 2 (CCL2), also known as, monocyte chemoattractant protein (MCP)-1, increases in response to disease-, trauma-, or toxicant-induced damage to the central nervous system (CNS). In the periphery, endogenous and exogenous glucocorticoids are known to suppress CCL2 expression associated with inflammatory conditions. However, such actions of glucocorticoids on CCL2 expression in the CNS remain unknown. Here, we explored the effects of the glucocorticoid, corticosterone (CORT), on the expression of CCL2 and its receptors, CCR2 and CCR5, in the hippocampal formation using intact, adrenalectomized (ADX) and trimethyltin (TMT)-treated rats. An immunosuppressive regimen of CORT did not alter the mRNA expression of CCL2 or its receptors in the hippocampus. ADX, however, markedly increased the expression of CCL2 and CCR2 mRNAs in the hippocampus, while CORT replacement reversed the effects of ADX on CCL2 gene expression. Hippocampal damage resulting from systemic administration of the organometallic neurotoxicant, TMT, was associated with microglial activation, as evidenced by enhanced expression of microglial markers integrin alphaM (CD11b) and F4/80, as well as, microglia-associated factors, CCL2 and IL-1alpha. An immunosuppressive dose of CORT, suppressed TMT-induced expression of CCL2. Given the association of CCL2 with microglial activation, it appears that CORT may play a role in regulating microglial activation. However, CORT treatment did not alter TMT-mediated neuronal damage and astrogliosis. Such observations suggest that injury-related expression of microglia-associated chemokines and cytokines may subserve a role unrelated to neuronal damage. In summary, our data indicate that in the CNS, CCL2 gene expression is under negative regulation by glucocorticoids.
Molecular Neurotoxicology Laboratory, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, CDC-NIOSH, TMBB-HELD, MS 3014, 1095 Willowdale Road, Morgantown, WV 26505, USA