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J. Biol. Chem., Vol. 282, Issue 20, 15208-15216, May 18, 2007

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Minocycline Down-regulates MHC II Expression in Microglia and Macrophages through Inhibition of IRF-1 and Protein Kinase C (PKC)_/II^*

Maria Nikodemova¹, Jyoti J. Watters, Samuel J. Jackson, Shaun K. Yang, and Ian D. Duncan

From the Departments of Medical Sciences and Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin, Madison, Wisconsin 53706

Experimental allergic encephalomyelitis, an autoimmune disorder mediated by T cells, results in demyelination, inflammation, and axonal loss in the central nervous system (CNS). Microglia play a critical role in major histocompatibility complex class II (MHC II)-dependent antigen presentation and in reactivation of CNS-infiltrated encephalitogenic T cells. Minocycline, a tetracycline anti-biotic, has profound anti-inflammatory properties and is experimentally used for treatment of many CNS disorders; however, the mechanisms involved in minocycline effects remain unknown. We show that administration of minocycline for 2 weeks ameliorated clinical severity of experimental allergic encephalomyelitis, an effect that partially involves the down-regulation of MHC II proteins in the spinal cord. Therefore, we sought to elucidate the molecular mechanisms of minocycline inhibitory effects on MHC II expression in microglia. Although complex, the co-activator class II transactivator (CIITA) is a key regulator of MHC II expression. Here we show that minocycline inhibited interferon (IFN)-induced CIITA and MHC II mRNA. Interestingly, however, it was without effect on STAT1 phosphorylation or IRF-1 expression, transcription factors that are activated by IFN and necessary for CIITA expression. Further experiments revealed that MHC II expression is down-regulated in the presence of the PKC inhibitor Gö6976. Minocycline inhibited IFN-induced PKC_/II phosphorylation and the nuclear translocation of both PKC_/II and IRF-1 that subsequently inhibits CIITA expression. Our present data delineate a molecular pathway of minocycline action that includes inhibitory effects on PKC_/II and transcription factors that regulate the expression of critical inflammatory genes such as MHC II. Such a fundamental mechanism may underlie the pleiotropic effects of minocycline in CNS inflammatory disorders.

Received for publication, December 29, 2006 , and in revised form, February 28, 2007.

^* This work was supported by the National Multiple Sclerosis Society Grant RG3472A8. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Medical Sciences, School of Veterinary Medicine, University of Wisconsin, 2015 Linden Drive, Madison, WI 53706. Tel.: 608-263-9829; Fax: 608-265-2474; E-mail: nikodemova{at}svm.vetmed.wisc.edu.

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