Pigment epithelium-derived factor induces the production of chemokines by rat microglia.
Many studies have shown that pigment epithelium-derived factor (PEDF) has neurotrophic effects on retinal cells and hippocampal, spinal cord, and cerebellar granule cell neurons, but much less work has examined the effects of PEDF on glia. In this study, we show that PEDF changes microglial morphology within 1 h of exposure, to a more deactivated form, while having no effect on the expression of such activation markers as OX-42 and ED-1. In contrast, urea activates acid phosphatase, and PEDF blocks that activation. PEDF also activates NFkappaB, accompanied by the induction of mRNAs and proteins for the chemokines macrophage inflammatory protein-1alpha (MIP-1alpha, MIP-2, and MIP-3alpha. All the chemokines stimulate acid phosphatase activity, and high doses of MIP-2 and MIP-3alpha), alter the morphology of the microglia at 1 h after treatment. These results suggest that the use of PEDF for clinical treatments, such as for retinal neovascularization, brain injury, or ischemia, should be undertaken with caution because of the possibility of induction of inflammation caused by microglial or other immune cell migration in response to the chemokines induced by PEDF.
Takanohashi
Asako
A
Neurotrophic Factors Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892-0151, USA.
Yabe
Takeshi
T
Schwartz
Joan P
JP
D000135:Acid Phosphatase / Q000037:antagonists & inhibitors / Q000378:metabolism; D021581:Active Transport, Cell Nucleus / Q000187:drug effects / Q000502:physiology; D000818:Animals; D001927:Brain Diseases / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D048430:Cell Shape / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018925:Chemokines / Q000276:immunology / Q000378:metabolism* / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D005136:Eye Proteins / Q000494:pharmacology*; D005911:Gliosis / Q000139:chemically induced / Q000276:immunology / Q000503:physiopathology; D018836:Inflammation Mediators / Q000494:pharmacology; D019402:Macrophage Inflammatory Proteins / Q000235:genetics / Q000378:metabolism; D017628:Microglia / Q000187:drug effects* / Q000276:immunology; D016328:NF-kappa B / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D009414:Nerve Growth Factors / Q000494:pharmacology*; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015843:Serpins / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology; D014508:Urea / Q000494:pharmacology; D000099174:Pigment Epithelium-Derived Factor
D000135:Acid Phosphatase; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018925:Chemokines; D005136:Eye Proteins; D018836:Inflammation Mediators; D019402:Macrophage Inflammatory Proteins; D016328:NF-kappa B; D009414:Nerve Growth Factors; D012333:RNA, Messenger; D015843:Serpins; D014508:Urea; D000099174:Pigment Epithelium-Derived Factor