| Abstract: | Microglia rapidly respond to CNS injury yet the mechanisms leading to their activation and inactivation remain poorly defined. In particular, few studies have established how interactions among inflammatory mediators affect the innate immune response of microglia. To begin to understand the hierarchy of cytokine signalling we examined the effects of several cytokines on purified newborn and adult rat microglia in vitro, and we have examined the microglial response to injury in mice deficient in the IL‐1 type 1 receptor (IL‐1R1). Using several indices of activation, we find that IL‐1β, TNF‐α, and IL‐6 are potent microglial activators. By contrast, TGF‐β1 did not activate the cells and when TGFβ1 was administered prior to IL‐1β, it blocked the effects of IL‐1β. However, TGFβ1 was ineffective in antagonizing IL‐6. In null mice lacking the IL‐1R1, microglia inefficiently responded to injury, and IL‐6 induction was severely curtailed. These data establish a model of hierarchical signalling, whereby constitutive expression of TGF‐β1 in the CNS maintains microglia in a resting state. IL‐1, while an important microglial activator, is modifiable, whereas, the downstream cytokine, IL‐6, is a strong stimulus that is unaffected by other modifiers of the innate immune response. Acknowledgements: Supported by NMSS award #RG 3837. |
