Parathyroid hormone and other agents that stimulate bone resorption function, at least in part, by inducing osteoblasts to secrete cytokines that stimulate osteoclast differentiation and activity. We previously demonstrated that parathyroid hormone induces expression by osteoblasts of interleukin-6 and leukemia inhibitory factor without affecting the 16 other cytokines that were examined. We also showed that stimulation of osteoclast activity by parathyroid hormone is dependent on activation of the cAMP signal transduction pathway and secretion of interleukin-6 by osteoblasts. In the current study, we demonstrate that the rapid and transient stimulation of interleukin-6 and leukemia inhibitory factor is inhibited by actinomycin D and superinduced by protein synthesis inhibitors, the classical characteristics of an immediate-early gene response. Moreover, activation of cAMP signal transduction by parathyroid hormone and parathyroid hormone-related protein is necessary and sufficient to induce both interleukin-6 and leukemia inhibitory factor. In addition, cAMP analogues as well as vasoactive intestinal peptide and isoproterenol, two neuropeptides that stimulate bone resorption by activating cAMP signal transduction in osteoblasts, also induce interleukin-6 and leukemia inhibitory factor in these cells. Taken together with our previous results, this study suggests that interleukin-6 is crucial for stimulation of bone resorption not only by parathyroid hormone, but also by parathyroid hormone-related protein, vasoactive intestinal peptide, and -adrenergic agonists, like isoproterenol.

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