Inflammatory cytokines: Putative regulators of neuronal and neuro- endocrine function

The cytokines are a large and diverse family of polypeptide regulators with multiple regulatory functions that have been comprehensively evaluated in the immune system under strictly controlled experimental conditions. These peptide signals exhibit often unpredictable interactions when evaluated for their pathophysiological involvement in specific inflammatory conditions in vivo. In our joint efforts to understand the basis for early pathophysiological changes in the brains of HIV-infected subjects, we have developed animal models for lentivirus infections, and assessed the actions of various cytokines acutely on transmitter release properties in vitro, and ill an in vivo transgenic mouse model. IL1β, IL2, IL6, and IFNα will each enhance the release of AVP in slices of rat hypothalamus and amygdala. TGFβ selectively blocks the ability of ACh to release AVP from hypothalamus or amygdala, but has no effects on the release stimulated by other cytokines. IFNα, but not TGFβ will also activate CRH release; as with AVP, TGF selectively blocks the ACh-stimulated CRH release in both amygdala and hypothalamus. The IFNα-stimulated release of AVP and CRH appears to be mediated by cyclic GMP production, and this release by IFNα and IL-2 may be mediated in part by activation of constitutive nitric oxide synthase. These combined in vitro actions would suggest that cns cytokine actions should upregulate the hypothalamic pituitary adrenal axis. In a transgenic mouse model with increased astrocytic expression 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 astrocytic uptake of the excitatory transmitter glutamate, the reactive oxygen species hydrogen peroxide and peroxynitrite, but not nitric oxide, inhibited 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 nitric oxide with a sustained increase in cytoplasmic free calcium. Thus while reactive oxygen species do provide a potential path to neurotoxicity 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.