In this study, we examined the role of cytokines, known to be in elevated levels in multiple sclerosis (MS) plaques, in regulating oligodendrocyte (ODC) expression of heat shock protein (hsp) in human brain-derived glial cell cultures. Using dual-stain immunohistochemistry, we initially compared the ability of a mixture of cytokines (IL-1 alpha, IL-1 beta, IL-2, IL-6, IL-8, TNF-alpha, TNF-beta, IFN-beta and IFN-gamma) with that of physical stimuli such as heat shock and peroxide, to increase cellular expression of the mainly inducible hsp72 species in mixed glial cell cultures (containing ODC, astrocytes and microglia). Similar to heat shock and peroxide, the cytokine mixture induced hsp72 expression only in ODC (70 +/- 5% vs. a baseline of 3 +/- 1% positive cells). When used individually, however, only IL-1 alpha (79 +/- 3%), IFN-gamma (70 +/- 2%) and TNF-alpha (65 +/- 5%) induced ODC hsp72 expression in mixed glial cell cultures. In purified ODC preparations, only IL-1 alpha induced hsp72 expression (84 +/- 4%). An IL-1 receptor antagonist (IL-1ra), abrogated hsp72 induction by IL-1 alpha (16 +/- 3%) as well as that due to IFN-gamma (14 +/- 1%) and TNF-alpha (13 +/- 2%) in mixed glial cell cultures. Furthermore, ODC express IL-1 receptors, detected by confocal laser scanning microscopy. Our data indicate that cytokines mediate hsp induction in ODC possibly via a final common pathway involving IL-1 binding to its receptor on ODC. Such interaction could enhance any putative ODC-immune interactions which are dependent on hsp molecule recognition.