tretinoin and Neuritis

It was investigated whether retinoic acid (RA) and the proinflammatory cytokines IL-1beta, IL-6, and TNFalpha influence the intracellular distribution of retinoic acid receptors (RAR) and retinoid X receptors (RXR) in Schwann cells. This question arose because nuclear translocation of RARalpha, RXRalpha, and RXRbeta was observed after nerve injury, and because mutual interactions exist between the signal transduction pathways of RA and proinflammatory cytokines. Schwann cell primary cultures from the rat sciatic nerve were incubated with IL-1beta, IL-6, and TNFalpha, with all-trans RA and with a combination of IL-1beta and RA. After incubation periods ranging from 5 min to 5 h, the intracellular distributions of RARalpha, RARbeta, RXRalpha, and RXRbeta were analyzed. All three cytokines caused a shift of RARalpha from the cytosolic compartments into the cell nuclei. This was also observed with RA, and combining RA with IL-1beta produced an additive effect. IL-1beta and IL-6 also affected the distribution of RARbeta, although immunoreactivity of this receptor always remained stronger in the cytosol. No effect of the cytokines on RXRalpha or RXRbeta was observed, whereas RA treatment caused a stronger nuclear signal of both receptors. Effects on the subcellular localization of retinoid receptors may provide a link in a feedback loop between RA/RAR and cytokines.

Topics: Active Transport, Cell Nucleus; Animals; Animals, Newborn; Cell Compartmentation; Cell Nucleus; Cells, Cultured; Cytokines; Drug Synergism; Feedback, Physiological; Interleukin-1beta; Interleukin-6; Neuritis; Peripheral Nerves; Rats; Rats, Sprague-Dawley; Receptors, Retinoic Acid; Retinoid X Receptors; Schwann Cells; Signal Transduction; Tretinoin; Tumor Necrosis Factor-alpha

Although Borrelia burgdorferi is found at the site of many manifestations of Lyme disease, local infection may not explain all features of the disease. Previous work has demonstrated that the organism's flagellin cross-reacts with a component of human peripheral nerve axon, heat shock protein 60. The cross-reacting epitope is identified by a single anti-B. burgdorferi flagellin monoclonal antibody, H9724. We now report that the spontaneous and peptide growth factor-stimulated in vitro neuritogenesis of SK-N-SH neuroblastoma cells and other neural tumor cell lines is suppressed by H9724. In contrast, changes induced by exposure of these cells to optimal and suboptimal concentrations of cyclic AMP, phorbol ester, or retinoic acid are not affected by H9724. H9724 does not decrease cell viability or the ability of the cells to anchor to the culture plate or extracellular matrix and does not block nerve growth factor binding to the cells. These findings are compatible with the premise that antiaxonal antibodies formed during the immune response to B. burgdorferi flagellin might modify axonal function in vivo and play a role in the pathogenesis of neurologic features of Lyme disease. A humoral immune response predicated on molecular mimicry could explain persistent or ongoing neurologic dysfunction occurring after elimination of the organism by appropriate antibiotic therapy.

Topics: Antibodies, Bacterial; Antibodies, Monoclonal; Autoantibodies; Autoimmunity; Axons; Borrelia burgdorferi Group; Cell Survival; Cyclic AMP; Extracellular Matrix; Fibroblast Growth Factor 2; Flagellin; Heat-Shock Response; Humans; Lyme Disease; Molecular Mimicry; Nerve Growth Factors; Neurites; Neuritis; Tetradecanoylphorbol Acetate; Tretinoin; Tumor Cells, Cultured