Involvement of glial cell line-derived neurotrophic factor in activation processes of rodent macrophages.
The physiological roles of glial cell line-derived neurotrophic factor (GDNF) expressed in the microglia/macrophages of the injured spinal cord have not yet been clarified. mRNA expression of chemokines, including monocyte chemoattractant protein (MCP)-1, was evoked within 1 hr after transection of the spinal cord, and GDNF mRNA expression was similarly up-regulated. Immunohistochemical analysis showed that GDNF was coexpressed with MCP-1 in the CD11b-positive cells. Therefore, we examined further the effects of GDNF on cultured rat peritoneal macrophages. GDNF enhanced the phagocytic activity of the macrophages via GFRalpha-1, glycosylphosphatidylinositol-anchored specific binding site of GDNF, in a c-Ret-independent manner. The influence of autocrine and/or paracrine GDNF synthesis was evaluated by performing activation experiments using macrophages cultured from heterozygous (+/-) GDNF gene-deficient mice or wild-type (+/+) mice. There were no morphological differences dependent on genetic types or stimulators. However, the GDNF mRNA level, but not the MCP-1 or GFRalpha-1 mRNA level, was substantially lower in the mutant macrophages than in the +/+ cells irrespective of stimulation with MCP-1 or lipopolysaccharide (LPS). The phagocytic activity enhanced by MCP-1 or LPS was significantly lower in the mutant cells (+/-) than in the +/+ ones, demonstrating the involvement of endogenous GDNF in the activation processes of macrophages in vitro and suggesting that not only neuroprotective function but also activation of macrophages is effected by the GDNF produced after a spinal cord injury.
Hashimoto
Manabu
M
Laboratory of Molecular Biology, Gifu Pharmaceutical University, Gifu, Japan.
Nitta
Atsumi
A
Fukumitsu
Hidefumi
H
Nomoto
Hiroshi
H
Shen
Liya
L
Furukawa
Shoei
S
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D039481:CD11b Antigen / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000378:metabolism; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D018925:Chemokines / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004789:Enzyme Activation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D007150:Immunohistochemistry / Q000379:methods; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D020932:Nerve Growth Factor / Q000235:genetics / Q000378:metabolism; D009414:Nerve Growth Factors / Q000172:deficiency / Q000494:pharmacology / Q000502:physiology*; D020933:Neurotrophin 3 / Q000235:genetics / Q000378:metabolism; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000502:physiology; D051096:Proto-Oncogene Proteins c-ret; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D020794:Receptor Protein-Tyrosine Kinases / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013119:Spinal Cord Injuries / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors
D019208:Brain-Derived Neurotrophic Factor; D039481:CD11b Antigen; C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D018925:Chemokines; C495040:Gdnf protein, mouse; C495041:Gdnf protein, rat; C494988:Gfra1 protein, mouse; C494989:Gfra1 protein, rat; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D005904:Glial Fibrillary Acidic Protein; D008070:Lipopolysaccharides; D009414:Nerve Growth Factors; D020933:Neurotrophin 3; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D020932:Nerve Growth Factor; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; C494999:Ret protein, mouse; C495001:Ret protein, rat; D010751:Phosphopyruvate Hydratase