Fc epsilon RII/CD23 is expressed in Parkinson's disease and induces, in vitro, production of nitric oxide and tumor necrosis factor-alpha in glial cells

Oxidative stress is thought to be involved in the mechanism of nerve cell d eath in Parkinson's disease (PD). Among several toxic oxidative species, ni tric oxide (NO) has been proposed as a key element on the basis of the incr eased density of glial cells expressing inducible nitric oxide synthase (iN OS) in the substantia nigra (SN) of patients with PD. However, the mechanis m of iNOS induction in the CNS is poorly understood, especially under patho logical conditions. Because cytokines and Fc epsilon RII/CD23 antigen have been implicated in the induction of iNOS in the immune system, we investiga ted their role in glial cells in vitro and in the SN of patients with PD an d matched control subjects. We show that, in vitro, interferon-gamma (IFN-g amma) together with interleukin-1 beta (Il-1 beta) and tumor necrosis facto r-alpha (TNF-alpha) can induce the expression of CD23 in glial cells. Ligat ion of CD23 with specific antibodies resulted in the induction of iNOS and the subsequent release of NO. The activation of CD23 also led to an upregul ation of TNF-alpha production, which was dependent on NO release. In the SN of PD patients, a significant increase in the density of glial cells expre ssing TNF-alpha, Il-1 beta, and IFN-gamma was observed. Furthermore, althou gh CD23 was not detectable in the SN of control subjects, it was found in b oth astroglial and microglial cells in parkinsonian patients. Altogether, t hese data demonstrate the existence of a cytokine/CD23-dependent activation pathway of iNOS and of proinflammatory mediators in glial cells and their involvement in the pathophysiology of PD.