Early growth response-2 (Egr-2) protein is a transcription factor, which belongs to Egr family which involve in modulating the peripheral immune response, by means of the induction of differentiation of lymphocyte precursors, activation of T and B cells. Egr-2 plays essential roles in peripheral nerve myelination, adipogenesis, tissue repair and fibrosis, immune tolerance; however, its regulation and role in central nervous system (CNS) remain poorly understood. In contrast to Egr-1, which has been extensively investigated, the regulation and function of Egr-2 remains less well characterized. To elaborate whether Egr-2 was involved in CNS injury, we performed a neuroinflammatory model by lipopolysaccharide (LPS) lateral ventral injection in adult rats. Egr-2 expression was strongly induced in active glia cells (astrocytes and microglias) in inflamed brain cortex. In vitro studies indicated that the upregulation of Egr-2 may be involved in the subsequent glia cellular activation following LPS exposure; and knock down of Egr-2 in primary mixed glial cultures (MGC) by siRNA showed that Egr-2 promoted the synthesis of TNF-α. Collectively, these results suggested Egr-2 may be important in host defense in CNS immune response, which might provide a potential target to the treatment of neuroinflammation.