Immunohistochemical localization of phosphorylated protein kinase R and phosphorylated eukaryotic initiation factor-2 alpha in the central nervous system of SJL mice with experimental allergic encephalomyelitis.

Inflammatory cells enter the CNS and target myelin in multiple sclerosis (MS) and experimental allergic encephalomyelitis (EAE), a model of MS, and inflammation is thought to induce stress responses in the CNS. Protein kinase R (PKR) and eukaryotic initiation factor-2 alpha (eIF2 alpha) undergo phosphorylation in response to stress, and the phosphorylated forms of these proteins play a key role in regulating protein synthesis. The objective of this study was to investigate the expression profile of phospho-PKR and phospho-eIF2 alpha during the course of EAE in order to advance the understanding of the stress response in this disease. In control animals (no encephalitogen with no emulsion; no encephalitogen with emulsion) and in preclinical EAE animals, phospho-PKR immunoreactivity was present in oligodendrocytes and some neurons, whereas, in EAE animals with active disease there was widespread labeling of inflammatory cells, and these cells were present during the recovery period of EAE, albeit to a lesser extent. Double-labeling studies revealed that T cells and a few macrophages were phospho-PKR(+). Phospho-eIF2 alpha immunoreactivity was detected in some oligodendrocytes in hindbrain sections of control animals. In EAE animals with active disease, the number of labeled oligodendrocytes increased, and inflammatory T cells also were labeled. Insofar as phospho-PKR activates nuclear factor-kappa B, it may facilitate cytokines expression by T cells. Alternatively, phospho-PKR and phospho-eIF2 alpha may promote apoptosis as a way to regulate T-cell number in the CNS. The expression of phospho-eIF2 alpha in oligodendrocytes during EAE likely is involved with inhibition of protein translation, which is a protective mechanism used to promote cell survival in response to inflammation. Copyright 2004 Wiley-Liss, Inc.