INFLAMMATORY CYTOKINES - PUTATIVE REGULATORS OF NEURONAL AND NEUROENDOCRINE FUNCTION

The cytokines are a large and diverse family of polypeptide regulators with multiple regulatory functions that have been comprehensively eva luated in the immune system under strictly controlled experimental con ditions. These peptide signals exhibit often unpredictable interaction s when evaluated for their pathophysiological involvement in specific inflammatory conditions in vivo. In our joint efforts to understand th e basis for early pathophysiological changes in the brains of HIV-infe cted subjects, we have developed animal models for lentivirus infectio ns, and assessed the actions of various cytokines acutely on transmitt er release properties in vitro, and in an in vivo transgenic mouse mod el. IL1 beta, IL2, IL6, and IFN alpha will each enhance the release of AVP in slices of rat hypothalamus and amygdala. TGF beta selectively blocks the ability of ACh to release AVP from hypothalamus or amygdala , but has no effects on the release stimulated by other cytokines. IFN alpha, but not TGF beta will also activate CRH release; as with AVP, TGF selectively blocks the ACh-stimulated CRH release in both amygdala and hypothalamus. The IFN alpha-stimulated release of AVP and CRH app ears to be mediated by cyclic GMP production, and this release by IFN alpha and IL-2 may be mediated in part by activation of constitutive n itric oxide synthase. These combined in vitro actions would suggest th at cns cytokine actions should upregulate the hypothalamic pituitary a drenal axis. In a transgenic mouse model with increased astrocytic exp ression and release of the cytokine IL6, the HPA axis is upregulated, but the effect seems attributable to adrenocortical hypersensitization to ACTH. Lastly, in studies of cytokine mediated effects on astrocyti c uptake of the excitatory transmitter glutamate, the reactive oxygen species hydrogen peroxide and peroxynitrite, but not nitric oxide, inh ibited glutamate uptake in a concentration-dependent manner. Although superoxide and nitric oxide had no effect by themselves on the rate of glutamate uptake by astrocytes, the same cultures did respond to nitr ic oxide with a sustained increase in cytoplasmic free calcium. Thus w hile reactive oxygen species do provide a potential path to neurotoxic ity but one apparently not involving nitric oxide. These various data provide important opportunities for early therapeutic interventions in neuro-inflammatory states such as Neuro-AIDS. (C) 1998 Elsevier Scien ce B.V. All rights reserved.