Differential effects of Th1, monocyte/macrophage and Th2 cytokine mixtures on early gene expression for glial and neural-related molecules in central nervous system mixed glial cell cultures: neurotrophins, growth factors and structural proteins.
BACKGROUND
In multiple sclerosis, inflammatory cells are found in both active and chronic lesions, and it is increasingly clear that cytokines are involved directly and indirectly in both formation and inhibition of lesions. We propose that cytokine mixtures typical of Th1 or Th2 lymphocytes, or monocyte/macrophages each induce unique molecular changes in glial cells.


METHODS
To examine changes in gene expression that might occur in glial cells exposed to the secreted products of immune cells, we have used gene array analysis to assess the early effects of different cytokine mixtures on mixed CNS glia in culture. We compared the effects of cytokines typical of Th1 and Th2 lymphocytes and monocyte/macrophages (M/M) on CNS glia after 6 hours of treatment.


RESULTS
In this paper we focus on changes with potential relevance for neuroprotection and axon/glial interactions. Each mixture of cytokines induced a unique pattern of changes in genes for neurotrophins, growth and maturation factors and related receptors; most notably an alternatively spliced form of trkC was markedly downregulated by Th1 and M/M cytokines, while Th2 cytokines upregulated BDNF. Genes for molecules of potential importance in axon/glial interactions, including cell adhesion molecules, connexins, and some molecules traditionally associated with neurons showed significant changes, while no genes for myelin-associated genes were regulated at this early time point. Unexpectedly, changes occurred in several genes for proteins initially associated with retina, cancer or bone development, and not previously reported in glial cells.


CONCLUSIONS
Each of the three cytokine mixtures induced specific changes in gene expression that could be altered by pharmacologic strategies to promote protection of the central nervous system.
Lisak
Robert P
RP
Department of Neurology, 8D University Health Center, Wayne State University School of Medicine, 4201 St Antoine, Detroit, MI 48210, USA. rlisak@med.wayne.edu
Benjamins
Joyce A
JA
Bealmear
Beverly
B
Nedelkoska
Liljana
L
Yao
Bin
B
Land
Susan
S
Studzinski
Diane
D
D000818:Animals; D000831:Animals, Newborn; D018929:Cell Culture Techniques; D002490:Central Nervous System / Q000166:cytology / Q000378:metabolism; D018920:Coculture Techniques; D016207:Cytokines / Q000096:biosynthesis* / Q000235:genetics; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis* / Q000235:genetics; D008264:Macrophages / Q000166:cytology / Q000378:metabolism*; D009000:Monocytes / Q000166:cytology / Q000378:metabolism*; D009414:Nerve Growth Factors / Q000096:biosynthesis* / Q000235:genetics; D009457:Neuroglia / Q000166:cytology / Q000502:physiology*; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D051381:Rats; D018417:Th1 Cells / Q000166:cytology / Q000378:metabolism; D018418:Th2 Cells / Q000166:cytology / Q000378:metabolism
D016207:Cytokines; D036341:Intercellular Signaling Peptides and Proteins; D009414:Nerve Growth Factors; D011506:Proteins