Proteoglycans participate in hematopoiesis and immune responses by mediating cell adhesion and by binding and presenting growth factors to cells. However, the mechanisms that regulate proteoglycan expression on cells of the immune system have not been defined. Syndecan-1, a member of the syndecan family of integral membrane proteoglycans, is expressed by pre-B cells and plasma cells but is absent from circulating B cells. Because IL-6 is an important cytokine in both B cell differentiation and in the progression of B cell-related diseases, we examined the effect of IL-6 on syndecan-1 expression. Following growth of murine B lymphoid cells in medium containing IL-6, the level of syndecan-1 detected is dramatically reduced. This reduction in syndecan-1 expression is dependent on the concentration of IL-6 present in the medium, with syndecan-1 levels being 2.5- to 5-fold lower than those of controls when cells are grown in media containing 10 and 1000 U/ml of IL-6, respectively. The effect of IL-6 on syndecan-1 expression is time dependent, with syndecan-1 levels declining over the first 48 hr. This trend is reversible because following removal of exogenous IL-6, syndecan-1 levels increase within 24 hr to 80% of their control levels. The regulation of syndecan-1 expression by IL-6 appears to be via post-transcriptional mechanisms because syndecan-1 mRNA levels are not decreased following growth of cells in the presence of IL-6. Furthermore, IL-6 does not alter syndecan- 1 structure and therefore its effect is different from that of TGF-β which alters syndecan-1 glycosylation but not the number of syndecan-1 molecules at the cell surface. We conclude that IL-6 participates in the regulation of syndecan-1 expression on B lymphoid cells and, given its broad distribution, IL-6 may regulate proteoglycan expression on other cell types as well. © 1994 Academic Press. All rights reserved.