Tumor necrosis factor-alpha: A potentially neurodestructive cytokine produced by glia in the human glaucomatous optic nerve head

Tumor necrosis factor-alpha (TNF-alpha) mediates a range of cellular respon ses, which have potentially detrimental consequences that affect multiple c ell types. To determine whether TNF-alpha contributes to glaucomatous optic neuropathy, we have studied the expression of this cytokine and its recept or, tumor necrosis factor receptor-1 (TNF-R1), in human glaucomatous optic nerve heads from patients with different stages of disease using double lab eling fluorescence immunohistochemistry. We have also investigated the abil ity of this cytokine to induce nitric oxide synthase (NOS-2) in cultured hu man optic nerve astrocytes by immunocytochemistry and immunoblot. Normal ti ssue showed constitutive expression of TNF-R1 in the vasculature of the opt ic nerve heads but no positive labeling for TNF-alpha. In the glaucomatous optic nerve heads, the expression of both TNF-alpha and TNF-R1 were apparen tly upregulated, primarily in glial fibrillary acidic protein (GFAP)-positi ve astrocytes, and appeared to parallel the progression of optic nerve dege neration. In eyes with severe glaucomatous damage, some HLA-DR positive mic roglia also contained TNF-alpha and TNF-R1. In the most severely damaged op tic nerve heads, the axons of the retinal ganglion cells contained TNF-R1 a nd, therefore, are direct targets for neurodegeneration caused by TNF-alpha . In vitro astrocytes constitutively express TNF-R1 and TNF-alpha stimulati on induces expression of NOS-2. We hypothesize that TNF-alpha contributes t o the progression of optic nerve degeneration in glaucoma by both a direct effect on the axons of the retinal ganglion cells and by inducing NOS-2 in astrocytes. GLIA 32:42-50, 2000. (C) 2000 Wiley-Liss, Inc.