ACTIVATED microglia regulate immune and inflammatory responses in the CNS under a variety of stresses due to infection, injury and disease. In this study, we show that a stress-inducible small heat shock protein, rr-crystallin, induces in vitro activation of microglia cultured from newborn rat brain. Exposure of microglia to alpha-crystallin resulted in an increased production nitric oxide (NO) and the expression of the inducible NO synthase (iNOS) as determined by Western blot and reverse transcriptase-polymerase chain reaction (RT-PCR) analyses. alpha-Crystallin also stimulated the synthesis of the pro-inflammatory cytokine, TNF alpha. The results presented showing microglial induction of the two key immune regulatory and inflammatory molecules, i.e., NO and TNF alpha, in response to a stress-inducible protein, suggest a link between environmental stress and the CNS immune response. NeuroReport 10:2869-2873 (C) 1999 Lippincott Williams & Wilkins.