Minocycline down-regulates MHC II expression in microglia and macrophages through inhibition of IRF-1 and protein kinase C (PKC)alpha/betaII.
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 interferongamma (IFNgamma)-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 IFNgamma and necessary for CIITA expression. Further experiments revealed that MHC II expression is down-regulated in the presence of the PKC(alpha) inhibitor Gö6976. Minocycline inhibited IFNgamma-induced PKC(alpha/betaII) phosphorylation and the nuclear translocation of both PKC(alpha/betaII) and IRF-1 that subsequently inhibits CIITA expression. Our present data delineate a molecular pathway of minocycline action that includes inhibitory effects on PKC(alpha/betaII) 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.
Nikodemova
Maria
M
Department of Medical Sciences, School of Veterinary Medicine, University of Wisconsin, Madison, Wisconsin 53706, USA. nikodemova@svm.vetmed.wisc.edu
Watters
Jyoti J
JJ
Jackson
Samuel J
SJ
Yang
Shaun K
SK
Duncan
Ian D
ID
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use; D017951:Antigen Presentation / Q000187:drug effects / Q000276:immunology; D002227:Carbazoles / Q000494:pharmacology; D020278:Demyelinating Autoimmune Diseases, CNS / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects* / Q000276:immunology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis* / Q000276:immunology; D007211:Indoles / Q000494:pharmacology; D050856:Interferon Regulatory Factor-1 / Q000276:immunology / Q000378:metabolism; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism* / Q000502:physiology; D017628:Microglia / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008911:Minocycline / Q000494:pharmacology* / Q000627:therapeutic use; D009687:Nuclear Proteins / Q000276:immunology / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011493:Protein Kinase C / Q000276:immunology / Q000378:metabolism*; D064546:Protein Kinase C beta; D051571:Protein Kinase C-alpha / Q000276:immunology / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D013997:Time Factors; D015534:Trans-Activators / Q000276:immunology / Q000378:metabolism
D000900:Anti-Bacterial Agents; D000893:Anti-Inflammatory Agents; D002227:Carbazoles; D004791:Enzyme Inhibitors; D000949:Histocompatibility Antigens Class II; D007211:Indoles; D050856:Interferon Regulatory Factor-1; C083728:MHC class II transactivator protein; D009687:Nuclear Proteins; D015534:Trans-Activators; C081021:Go 6976; D007371:Interferon-gamma; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D051571:Protein Kinase C-alpha; D008911:Minocycline