Research

Differential effects of Th1, monocyte/macrophage and Th2 cytokine mixtures on early gene expression for molecules associated with metabolism, signaling and regulation in central nervous system mixed glial cell cultures

Robert P Lisak^1,2 , Joyce A Benjamins^1,2,3 , Beverly Bealmear¹ , Liljana Nedelkoska¹ , Diane Studzinski^1,6,7 , Ernest Retland¹ , Bin Yao^4,5 and Susan Land^4,5

¹  Department of Neurology, 8D University Health Center, Wayne State University School of Medicine, 4201 St Antoine, Detroit, MI, 48210, USA

²  Department of Immunology and Microbiology, Wayne State University School of Medicine, 540 E Canfield Avenue, Detroit, MI 48201, USA

³  Department of Biochemistry and Molecular Biology, Wayne State University School of Medicine, 540 E Canfield Avenue, Detroit, MI 48201, USA

⁴  Applied Genomics Technology Center, 5107 Biological Sciences, Wayne State University, 5047 Gullen Mall, Detroit MI 48202, USA

⁵  Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, 540 E Canfield, Detroit, MI 48201, USA

⁶  Department of Surgery, 6C University Health Center, Wayne State University School of Medicine, 4201 St Antoine, Detroit MI, US 48201, USA

⁷  Department of Surgery, William Beaumont Hospital, 3601 W Thirteen Mile Rd, Royal Oak MI 48073, USA

author email corresponding author email

Journal of Neuroinflammation 2009, 6:4doi:10.1186/1742-2094-6-4

Published:	21 January 2009

Abstract

Background

Cytokines secreted by immune cells and activated glia play central roles in both the pathogenesis of and protection from damage to the central nervous system (CNS) in multiple sclerosis (MS).

Methods

We have used gene array analysis to identify the initial direct effects of cytokines on CNS glia by comparing changes in early gene expression in CNS glial cultures treated for 6 hours with cytokines typical of those secreted by Th1 and Th2 lymphocytes and monocyte/macrophages (M/M).

Results

In two previous papers, we summarized effects of these cytokines on immune-related molecules, and on neural and glial related proteins, including neurotrophins, growth factors and structural proteins. In this paper, we present the effects of the cytokines on molecules involved in metabolism, signaling and regulatory mechanisms in CNS glia. Many of the changes in gene expression were similar to those seen in ischemic preconditioning and in early inflammatory lesions in experimental autoimmune encephalomyelitis (EAE), related to ion homeostasis, mitochondrial function, neurotransmission, vitamin D metabolism and a variety of transcription factors and signaling pathways. Among the most prominent changes, all three cytokine mixtures markedly downregulated the dopamine D3 receptor, while Th1 and Th2 cytokines downregulated neuropeptide Y receptor 5. An unexpected finding was the large number of changes related to lipid metabolism, including several suggesting a switch from diacylglycerol to phosphatidyl inositol mediated signaling pathways. Using QRT-PCR we validated the results for regulation of genes for iNOS, arginase and P glycoprotein/multi-drug resistance protein 1 (MDR1) seen at 6 hours with microarray.

Conclusion

Each of the three cytokine mixtures differentially regulated gene expression related to metabolism and signaling that may play roles in the pathogenesis of MS, most notably with regard to mitochondrial function and neurotransmitter signaling in glia.