Tumor necrosis factor-alpha regulation of the Id gene family in astrocytesand microglia during CNS inflammatory injury

The inhibitors of DNA binding (Id) gene family is highly expressed during e mbryogenesis and throughout adulthood in the rat central nervous system (CN S). In vitro studies suggest that the Id gene family is involved in the reg ulation of cell proliferation and differentiation. Recently, Id gene expres sion was shown to be expressed in immature and mature astrocytes during dev elopment and upregulated in reactive astrocytes after spinal cord injury. T hese results suggest that the Id gene family may play an important role in regulating astrocyte development and reactivity; however, the factors regul ating Id expression in astrocytes remain undefined. Tumor necrosis factor-a lpha (TNF alpha), a proinflammatory cytokine, is thought to play a crucial role in astrocyte/microglia activation after injury to the CNS. To determin e if TNF alpha plays a role in Id gene expression, we exogenously administe red TNF alpha into developing postnatal rats. We report that TNF alpha inje ctions resulted in a rapid and transient increase in both cell number and m RNA expression for Id2 and Id3 when compared to levels observed in noninjec ted or control-injected animals. Idl mRNA levels were also upregulated afte r TNF alpha treatment, but to a lesser degree. Significant increases in TNF alpha-induced Id2 and Id3 mRNA were observed in the ventricular/subventric ular zone, cingulum and corpus callosum. TNF alpha also increased Id2 mRNA expression in the caudate putamen and hippocampus at the injection site, Id 2 and Id3 mRNA+ cells were identified as GFAP+ and S100 alpha+ astrocytes a s well as ED1+ microglia. This is the first report to show TNF-alpha-induce d modulation of the Id gene family and suggests that Id may be involved in the formation of reactive astrocytes and activated microglia in the rodent brain. These results suggest a putative role for the Id family in the molec ular mechanisms regulating cellular responsiveness to TNF alpha and CNS inf lammation. GLIA 26:139-152, 1999. (C) 1999 Wiley-Liss, Inc.