Ciliary neurotrophic factor and interleukin-6 differentially activate microglia

Abstract

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‐α (TNFα), interleukin‐1β (IL‐1β), and cyclooxygenase 2 (COX‐2) following stimulation. We show that CNTF reduces COX‐2 levels, whereas IL‐6 increases the expression of IL‐1β, TNFα, 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.