TY - JOUR
T1 - Insulin-like growth factor 1 and 2 (IGF1, IGF2) expression in human microglia
T2 - Differential regulation by inflammatory mediators
AU - Suh, Hyeon Sook
AU - Zhao, Meng Liang
AU - Derico, Leandra
AU - Choi, Namjong
AU - Lee, Sunhee C.
N1 - Funding Information:
The authors thank the Einstein Human Fetal Tissue Repository (Dr. Brad Poulos) and the National NeuroAIDS Tissue Consortium (Manhattan HIV Brain Bank, Dr. Susan Morgello) for providing tissues for this study. We are grateful to Drs. Sanjeev Gupta and Kathleen Whitney for providing control tissue and reagents for this study, and to Drs. Scott Letendre and Howard Strickler for helpful discussions. This study was supported by the NIH grants KO1MH084705, RO1MH55477, Einstein CFAR (P30AI051519), and a pilot grant from Einstein CFAR.
PY - 2013/3/12
Y1 - 2013/3/12
N2 - 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.
AB - 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.
KW - Brain
KW - Cytokines
KW - Growth factors
KW - HIV
KW - Human
KW - IGF1
KW - IGF2
KW - Inflammation
KW - LPS
KW - Microglia
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UR - http://www.scopus.com/inward/citedby.url?scp=84874776157&partnerID=8YFLogxK
U2 - 10.1186/1742-2094-10-37
DO - 10.1186/1742-2094-10-37
M3 - Article
C2 - 23497056
AN - SCOPUS:84874776157
SN - 1742-2094
VL - 10
JO - Journal of Neuroinflammation
JF - Journal of Neuroinflammation
M1 - 805
ER -
