title: Insulin-like growth factor 1 and 2 (IGF1, IGF2) expression in human microglia: differential regulation by inflammatory mediators.
abstract: BACKGROUND
  Recent studies in experimental animals show that insulin-like growth factor 1 (IGF1) plays a trophic role during development and tissue injury and that microglia are important sources of IGF1. However, little information is available regarding the expression, regulation, and function of IGF1 and related proteins in human brain cells. In the current study, we examined the expression of IGF1 and IGF2 in human microglia in vivo and in vitro.
  
  
  METHODS
  Expression of IGF1 and IGF2 was examined by immunohistochemistry in post-mortem human brain sections derived from HIV+ and HIV- brains. In primary cultures of human fetal microglia, IGF1 and IGF2 mRNA and protein expression was examined by Q-PCR, ELISA, and Western blot analysis. Additionally, the role of IGF1 and IGF2 in neuroprotection was examined in primary human neuronal glial cultures.
  
  
  RESULTS
  Immunohistochemistry of human brain tissues showed that nonparenchymal cells (vessels and meninges), as well as parenchymal microglia and macrophages were positive for IGF1, in both HIV encephalitis and control brains, while IGF2 was undetectable. Cultured microglia expressed IGF1 mRNA and produced pg/ml levels of IGF1 protein; this was significantly suppressed by proinflammatory mediators, such as lipopolysaccharide (LPS), poly(I:C), and IFNγ. The Th2 cytokines IL-4 and IL-13 had no significant effect, but the cAMP analog (dibutyryl cAMP) significantly increased IGF1 production. In contrast, microglial IGF2 mRNA and protein (determined by Western blot) were upregulated by LPS. IGF1 receptor (IGF1R) immunoreactivity was predominantly expressed by neurons, and both IGF1 and IGF2 significantly protected neurons from cytokine (IL-1/IFNγ) induced death.
  
  
  CONCLUSIONS
  Our study in human brain tissues and cells indicates that microglia are important sources of neurotrophic growth factors IGF1 and IGF2, and that microglial activation phenotypes can influence the growth factor expression. Importantly, our results suggest that chronic neuroinflammation and upregulation of proinflammatory cytokines could lead to neurodegeneration by suppressing the production of microglia-derived neuronal growth factors, such as IGF1.
authors.affiliation: Department of Pathology, Albert Einstein College of Medicine, Bronx, NY 10461, USA. hyeon-sook.suh@einstein.yu.edu
authors.forename: Hyeon-Sook
authors.initials: HS
authors.lastname: Suh
authors.forename: Meng-Liang
authors.initials: ML
authors.lastname: Zhao
authors.forename: Leandra
authors.initials: L
authors.lastname: Derico
authors.forename: Namjong
authors.initials: N
authors.lastname: Choi
authors.forename: Sunhee C
authors.initials: SC
authors.lastname: Lee
mesh_terms: D002478:Cells, Cultured; D018920:Coculture Techniques; D005786:Gene Expression Regulation; D006801:Humans; D018836:Inflammation Mediators / Q000502:physiology*; D007334:Insulin-Like Growth Factor I / Q000096:biosynthesis* / Q000235:genetics; D007335:Insulin-Like Growth Factor II / Q000096:biosynthesis* / Q000235:genetics; D017628:Microglia / Q000378:metabolism* / Q000473:pathology; D009457:Neuroglia / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010641:Phenotype
chemical_list: C035170:IGF2 protein, human; D018836:Inflammation Mediators; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II