Ciliary neurotrophic factor and interleukin-6 differentially activate microglia.
Studies have shown that cytokines released following CNS injury can affect the supportive or cytotoxic functions of microglia. Interleukin-6 (IL-6)-family cytokines are among the injury factors released. To understand how microglia respond to IL-6 family cytokines, we examined the effects of ciliary neurotrophic factor (CNTF) and IL-6 on primary cultures of rat microglia. To assess the functional state of the cells, we assayed the expression of tumor necrosis factor-alpha (TNFalpha), interleukin-1beta (IL-1beta), and cyclooxygenase 2 (COX-2) following stimulation. We show that CNTF reduces COX-2 levels, whereas IL-6 increases the expression of IL-1beta, TNFalpha, and Cox-2. We also examined trophic factor expression and found that CNTF enhances glial cell-line derived neurotrophic factor (GDNF) mRNA and protein secretion, whereas IL-6 has no effect. Correspondingly, conditioned media from CNTF-stimulated microglia promote motor neuron survival threefold beyond controls, whereas IL-6-stimulated microglia decrease neuronal survival twofold. To understand better the signaling mechanisms responsible for the opposite responses of these IL-6-family cytokines, we examined STAT-3 and ERK phosphorylation in CNTF- and IL-6-stimulated microglia. IL-6 markedly increases STAT-3 and ERK phosphorylation after 20 min of treatment, whereas these signal transducers are weakly stimulated by CNTF across a range of doses. We conclude that CNTF modifies microglial activation to support neuronal survival and that IL-6 enhances their capacity to do harm, as a result of different modes of intracellular signaling.
Krady
J Kyle
JK
Department of Neural and Behavioral Sciences, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA.
Lin
Hsiao-Wen
HW
Liberto
Christina M
CM
Basu
Anirban
A
Kremlev
Sergey G
SG
Levison
Steven W
SW
D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D002540:Cerebral Cortex; D020934:Ciliary Neurotrophic Factor / Q000494:pharmacology*; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D004622:Embryo, Mammalian; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000494:pharmacology*; D017628:Microglia / Q000187:drug effects*; D009046:Motor Neurons / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
D020934:Ciliary Neurotrophic Factor; D051100:Glial Cell Line-Derived Neurotrophic Factor; D053583:Interleukin-1beta; D015850:Interleukin-6; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D051546:Cyclooxygenase 2