Vitamin D Inhibits Expression of Protein Arginine Deiminase 2 and 4 in Experimental Autoimmune Encephalomoyelitis Model Of Multiple Sclerosis

Multiple sclerosis (MS) is a disabling disease that afflicts an estimated two million people worldwide. The disease is characterized by degradation of the myelin sheath that insulates neurons of the central nervous system manifesting as a heterogeneous collection of symptoms. Two enzymes, protein arginine deaminases type 2 and 4 (PAD2 and PAD4) have been implicated to play an etiologic role in demyelination and neurodegeneration by catalyzing a post-translational modification of arginine peptide residues to citrulline. The pathogenesis of MS is poorly understood, though vitamin D deficiency is a well-associated risk factor for developing the disorder. Using the experimental autoimmune encephalomyelitis (EAE) model of MS we demonstrate vitamin D treatment to attenuate over-expression of PAD 2 and 4 in the brain and spine during EAE. In addition, we identify two molecules produced by peripheral immune cells, IFNɣ and IL-6, as candidate signaling molecules that induce PAD expression in the brain. We demonstrate vitamin D treatment to inhibit IFNɣ mediated up regulation of PAD2 and PAD4 both directly within the brain and by modulating PAD-inducing cytokine production by infiltrating immune cells. These results provide neuroprotective rational for the supplementation of vitamin D in MS patients. More importantly, these results imply an epigenetic link between vitamin D deficiency and the pathogenesis of MS that merits further investigation.

Author dc:creator

• McCain, Travis William

Advisor dc:contributor.advisor

• Gallagher, Patricia J.

• PAD2, PAD4, protein arginine deiminase, peptidyl arginine deiminase, vitamin D, 1,25(OH)2D3, multiple sclerosis, MS, EAE, experimental autoimmune encephalomyelitis, epigenetics, methylation, citrullination, citrulline

Statement dc:rights

• Attribution-NoDerivs 3.0 United States

Licence dc:rights.uri

• http://creativecommons.org/licenses/by-nd/3.0/us/

Language dc:language.iso

en_US

Identifier URI

http://dx.doi.org/10.7912/C2/2013

OAI identifier oai:identifier

oai:scholarworks.indianapolis.iu.edu:1805/6018