INSULIN-LIKE GROWTH FACTOR-I ACTIVITY IS INHIBITED BY INTERLEUKIN-1-ALPHA, TUMOR-NECROSIS-FACTOR-ALPHA, AND INTERLEUKIN-6

With evidence that several proteins inhibit insulin-like growth factor (IGF) activity, we evaluated whether cytokines, which are elevated in many catabolic states, also affect IGF-1-mediated proteoglycan synthe sis. Cartilage from hypophysectomized rats was exposed to the cytokine s interleukin-1alpha (IL-1alpha), tumor necrosis factor-alpha (TNF-alp ha) or interleukin-6 (IL-6) in the presence or absence of IGF-1. IL-1a lpha inhibited IGF-1-stimulated proteoglycan (PG) synthesis > 95% at 2 0 ng/ml (p < 0.01). TNF-alpha and IL-6 caused a maximum inhibition of 56 and 54%, respectively, both at 200 ng/ml. Only in the absence of IG F-1 did IL-1alpha inhibit PG synthesis below unstimulated levels, sugg esting that although IL-1alpha can directly inhibit PG synthesis, IL-1 alpha, TNF-alpha, TNF-alpha, and IL-6 each promotes cartilage loss als o by inhibiting IGF-1-mediated anabolism.