Interference with RhoA-ROCK signaling mechanism in autoreactive CD4+ T cells enhances the bioavailability of 1,25-dihydroxyvitamin D3 in experimental autoimmune encephalomyelitis

Am J Pathol. 2012 Sep;181(3):993-1006. doi: 10.1016/j.ajpath.2012.05.028. Epub 2012 Jul 13.


Vitamin D deficiency is a major risk factor for central nervous system (CNS) demyelinating diseases including multiple sclerosis (MS) and its animal model, that of experimental autoimmune encephalomyelitis (EAE). Both vitamin D(3) and 1, 25-dihydroxyviatmin-D(3) (calcitriol) had beneficial effects in EAE/MS. However, the exact cause of vitamin D deficiency in EAE/MS is not clear. Previously, we documented that lovastatin (LOV) provides protection in EAE animals via inhibition of RhoA-ROCK signaling. Herein, we demonstrate that LOV prevents the lowering of circulating 25-hydroxyvitamin-D(3) and 1,25-dihydroxyviatmin-D(3) levels including 1,25-dihydroxyviatmin-D(3) levels in the peripheral lymphoid organs and CNS of treated EAE animals. These effects of LOV were attributed to enhanced expression of vitamin D synthesizing enzyme (1α-hydroxylase) in kidney and the CNS, with corresponding reduction of vitamin D catabolizing enzyme (24-hydorxylase) expression in the CNS of EAE animals via inhibition of RhoA-ROCK signaling. Ex vivo and in vitro studies established that autoreactive Th1/Th17 cells had higher expression of 24-hydroxylase than Th2/T regulatory cells, that was reverted by LOV or ROCK inhibitor. Interestingly, LOV-mediated regulation of vitamin D metabolism had improved vitamin D(3) efficacy to confer protection in EAE animals and that was ascribed to the LOV- and calcitriol-induced immunomodulatory synergy. Together, these data provide evidence that interfering with RhoA-ROCK signaling in autoreactive Th1/Th17 cells can improve vitamin D(3) efficacy in clinical trials of MS and related neurodegenerative disorders.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • 25-Hydroxyvitamin D3 1-alpha-Hydroxylase / metabolism
  • Animals
  • Biological Availability
  • Biosynthetic Pathways / drug effects
  • CD4-Positive T-Lymphocytes / drug effects
  • CD4-Positive T-Lymphocytes / microbiology*
  • Calcitriol / pharmacology
  • Encephalomyelitis, Autoimmune, Experimental / blood
  • Encephalomyelitis, Autoimmune, Experimental / enzymology*
  • Encephalomyelitis, Autoimmune, Experimental / immunology*
  • Female
  • Guinea Pigs
  • Immunosuppression Therapy
  • Inflammation / pathology
  • Lovastatin / pharmacology
  • Lymphoid Tissue / drug effects
  • Lymphoid Tissue / metabolism
  • Lymphoid Tissue / pathology
  • Mevalonic Acid / metabolism
  • Protein Kinase Inhibitors / pharmacology
  • Rats
  • Rats, Inbred Lew
  • Signal Transduction* / drug effects
  • Spinal Cord / drug effects
  • Spinal Cord / enzymology
  • Spinal Cord / pathology
  • Steroid Hydroxylases / metabolism
  • Vitamin D / analogs & derivatives*
  • Vitamin D / blood
  • Vitamin D / pharmacokinetics
  • Vitamin D3 24-Hydroxylase
  • rho-Associated Kinases / antagonists & inhibitors
  • rho-Associated Kinases / metabolism*
  • rhoA GTP-Binding Protein / metabolism*


  • Protein Kinase Inhibitors
  • dihydroxy-vitamin D3
  • Vitamin D
  • Lovastatin
  • Steroid Hydroxylases
  • Vitamin D3 24-Hydroxylase
  • 25-Hydroxyvitamin D3 1-alpha-Hydroxylase
  • rho-Associated Kinases
  • rhoA GTP-Binding Protein
  • Calcitriol
  • Mevalonic Acid