Bioactivity of Insulin-like growth factors (IGEs) are positively or negatively regulated by IGF binding proteins (IGFBPs). Like IGFs, production of IGFBPs are influenced by a number of hormonal factors. We studied the effects of cytokines on production of IGFBPs in human fibroblasts in culture. Both IL-1beta and TNF-alpha inhibited IGFBP-3 (42/38 KDa species) production in a concentration dependent manner judged by Western ligand blot. Expression of IGFBP-3 mRNA was also decreased by these cytokines. Moreover, the treatment with IL-1beta and TNF-alpha resulted in appearance of smaller mol weight (26 KDa) immunoreactive IGFBP-3 fragment(s) which lacked the ability to bind 125I-IGFs, indicating that these cytokines degrade IGFBP-3 via activation of proteases. Both IL-1beta and TNF-alpha decreased production of IGFBP-4, whereas they increased that of IGFBP-6, IL-6 had little effect on production of IGFBPs. Likewise, interferon-gamma failed to affect of production of IGFBPs except at high concentrations. The present data demonstrate that cytokines, especially IL-1beta and TNF-alpha are potent regulators of IGFBPs production and degradation. These cytokines may alter tissue uptake of IGFs and help to counteract the catabolic state induced by them.