Recent studies have revealed the potential importance of the extracellular matrix (ECM) in the modulation of mesangial cell (MC) function. Interleukin-6 (IL-6) is produced by MCs and was shown to induce MC proliferation, acting as an autocrine growth factor. Heparin is a known inhibitor of MC proliferation. It was shown to modulate ECM synthesis by cultured MCs. The action of heparin on IL-6 synthesis by MCs is presently unknown. We investigated the effect of heparin on IL-6 production when MCs were cultured with or without type-IV collagen, a major constituent of ECM. When MCs were cultured without coating, heparin significantly decreased their IL-6 production; on type-IV collagen, heparin had no significant effect. When tumor necrosis factor alpha (TNF-alpha) was used to stimulate the cells to produce IL-6, heparin was able to decrease the stimulatory effect of TNF-alpha when the cells were cultured on plastic but not when in contact with type-IV collagen. Thus we conclude that heparin has an inhibitory effect on IL-6 secretion by MCs that is prevented by type-IV collagen.