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

Abstract

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 antibiotic, 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.

Lipopolysaccharide-induced depressive-like behavior is mediated by indoleamine 2,3-dioxygenase activation in mice

“…IFN-g and TNF-a are the main inducers of IDO activation. 5,6 Minocycline has already been shown to block IFN-g-mediated protein kinase C (a/bII) phosphorylation and nuclear translocation of both protein kinase C (a/bII) and IRF-1, 17 which is necessary for IDO activation. It also inhibits nuclear factor k-B and MAP kinase activation, 35 which are both necessary for the synergistic effects of TNF-a and IFN-g on IDO activation.…”

“…Minocycline has potent anti-inflammatory effects independent from its microbicidal properties, as it is well-known to inhibit macrophage and microglial activation. Of all the tetracyclines, it has the greatest permeability through the blood-brain barrier, 17 and it confers therapeutic benefits in many CNS disease models, including ischemia, 18 Parkinson disease, 19 amyotrophic lateral sclerosis 20 and multiple sclerosis. 17 The tryptophan analog 1-methyltryptophan (1-MT) was chosen for the second approach.…”

“…Of all the tetracyclines, it has the greatest permeability through the blood-brain barrier, 17 and it confers therapeutic benefits in many CNS disease models, including ischemia, 18 Parkinson disease, 19 amyotrophic lateral sclerosis 20 and multiple sclerosis. 17 The tryptophan analog 1-methyltryptophan (1-MT) was chosen for the second approach. 1-MT, a competitive inhibitor of IDO, blocks human dendritic cell regulatory function in vitro 21 and functions in vivo to block IDO-mediated immune events in animal models of rheumatoid arthritis, 22 type 1 diabetes 23 and multiple sclerosis.…”

Tetracyclines Convert the Osteoclastic-Differentiation Pathway of Progenitor Cells To Produce Dendritic Cell-like Cells

“…They also suggested that tetracyclines induce DC-like cell differentiation at sites of RANKL expression. In addition, tetracyclines were shown to suppress inflammation (46)(47)(48)(49). The development of a drug-delivery system for tetracyclines will facilitate their use in the suppression of bone loss induced by local inflammation, including rheumatoid arthritis and periodontitis.…”

Regulating the Activity of Class II Transactivator by Posttranslational Modifications: Exploring the Possibilities

“…The study of CIITA modifications would benefit from similar strategies. Given the diverse range of genes regulated by CIITA, it is perceivable that dysregulated CIITA activity has been implicated in multiple pathophysiological processes, which include cancer (17,36), atherosclerosis (3,14), encephalitis (28), encephalomyelitis (20), carditis (5), and pulmonary fibrosis (Xu and Smith, unpublished). Because CIITA activity is modulated by the PTM machinery, it is now possible to target a host of PTM components in the development and/or optimization of therapeutic interventions against these pathologies.…”