Parathyroid hormone (1-34)–mediated interleukin-6 induction

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Abstract
Parathyroid hormone (PTH) functions in part by regulating osteoblast cytokine expression. We recently demonstrated that PTH induced a rapid and transient increase in interleukin‐6 (IL‐6) mRNA expression in rat bones in vivo. To determine the molecular basis of this effect, we analyzed the human IL‐6 promoter fused (−1,179 to +9) with the chloramphenicol acetyltransferase (CAT) reporter gene in stable transfections into human osteoblast‐like osteosarcoma SaOS‐2 cells. We compared the effects of PTH on IL‐6 expression with adenylate cyclase activator forskolin, PKC activator phorbol 12‐myristate 13‐acetate (PMA), calcium ionophore A23187, interleukin‐1α (IL‐1α), prostaglandin E‐2 (PGE‐2), RS‐66271 (a parathyroid hormone–related peptide analog), and platelet‐derived growth factor‐BB (PDGF‐BB). Analyses of cell clones showed that IL‐6 promoter expression was extremely low in the unstimulated state. Exposure to PTH (0.001–100 nM) for 12 h stimulated CAT expression in a dose‐dependent manner (200–500% of control). Treatment with IL‐1α was more potent than PTH in inducing transcription of the IL‐6 promoter (900–1,000%). Activation of the cAMP‐PKA pathway by treatment with forskolin induced a comparable level of induction with PTH. Together, the effects of PTH and forskolin were additive. RS‐66271, previously shown to have PTH‐like effects, induced a comparable level of IL‐6 promoter expression. When examined together, PTH + RS‐66271 effects were comparable to PTH effects alone. Exposure to PGE‐2, PMA, PDGF‐BB, or A23187 for 12 h did not significantly alter IL‐6 promoter expression. These results demonstrate PTH, forskolin, the PTHrP analog RS‐66271, and IL‐1α stimulate IL‐6 expression by stimulating gene transcription. The response to forskolin suggests that the messenger system mediated by PKA is sufficient to induce IL‐6 expression. J. Cell. Biochem. 67:265–274, 1997.