Dual role of Response gene to complement-32 in multiple sclerosis

Exp Mol Pathol. 2013 Feb;94(1):17-28. doi: 10.1016/j.yexmp.2012.09.005. Epub 2012 Sep 19.

Abstract

Response gene to complement (RGC)-32 is a novel molecule that plays an important role in cell proliferation. We investigated the expression of RGC-32 in multiple sclerosis (MS) brain and in peripheral blood mononuclear cells (PBMCs) obtained from patients with relapsing-remitting multiple sclerosis. We found that CD3(+), CD68(+), and glial fibrillar acidic protein (GFAP)(+) cells in MS plaques co-localized with RGC-32. Our results show a statistically significant decrease in RGC-32 mRNA expression in PBMCs during relapses when compared to the levels in stable MS patients. This decrease might be useful in predicting disease activity in patients with relapsing-remitting MS. RGC-32 expression was also correlated with that of FasL mRNA during relapses. FasL mRNA expression was significantly reduced after RGC-32 silencing, indicating a role for RGC-32 in the regulation of FasL expression. In addition, the expression of Akt1, cyclin D1, and IL-21 mRNA was significantly increased during MS relapses when compared to levels in healthy controls. Furthermore, we investigated the role of RGC-32 in TGF-β-induced extracellular matrix expression in astrocytes. Blockage of RGC-32 using small interfering RNA significantly inhibits TGF-β induction of procollagen I, fibronectin and of the reactive astrocyte marker α-smooth muscle actin (α-SMA). Our data suggest that RGC-32 plays a dual role in MS, both as a regulator of T-cells mediated apoptosis and as a promoter of TGF-β-mediated profibrotic effects in astrocytes.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Actins / metabolism
  • Adolescent
  • Adult
  • Aged
  • Antigens, CD / analysis
  • Antigens, Differentiation, Myelomonocytic / analysis
  • Apoptosis
  • Astrocytes / metabolism
  • Brain / metabolism*
  • CD3 Complex / analysis
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism*
  • Cell Proliferation
  • Collagen Type I / metabolism
  • Complement System Proteins / metabolism
  • Cyclin D1 / biosynthesis
  • Cyclin D1 / genetics
  • Extracellular Matrix / metabolism
  • Fas Ligand Protein / genetics
  • Female
  • Fibronectins / metabolism
  • Glial Fibrillary Acidic Protein
  • Humans
  • Interleukins / biosynthesis
  • Interleukins / genetics
  • Leukocytes, Mononuclear / metabolism*
  • Male
  • Middle Aged
  • Multiple Sclerosis, Relapsing-Remitting / metabolism*
  • Muscle Proteins / genetics
  • Muscle Proteins / metabolism*
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Proto-Oncogene Proteins c-akt / biosynthesis
  • Proto-Oncogene Proteins c-akt / genetics
  • RNA Interference
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • RNA, Small Interfering
  • T-Lymphocytes / metabolism
  • Transforming Growth Factor beta / metabolism
  • Young Adult

Substances

  • ACTA2 protein, human
  • Actins
  • Antigens, CD
  • Antigens, Differentiation, Myelomonocytic
  • CD3 Complex
  • CD68 antigen, human
  • Cell Cycle Proteins
  • Collagen Type I
  • FASLG protein, human
  • Fas Ligand Protein
  • Fibronectins
  • Glial Fibrillary Acidic Protein
  • Interleukins
  • Muscle Proteins
  • Nerve Tissue Proteins
  • RGCC protein, human
  • RNA, Messenger
  • RNA, Small Interfering
  • Transforming Growth Factor beta
  • Cyclin D1
  • Complement System Proteins
  • Akt1 protein, mouse
  • Proto-Oncogene Proteins c-akt
  • interleukin-21