IL-13 AND IL-4 INHIBIT BONE-RESORPTION BY SUPPRESSING CYCLOOXYGENASE-2-DEPENDENT PROSTAGLANDIN SYNTHESIS IN OSTEOBLASTS

Activated T cells secrete the cytokine IL-13, which regulates inflamma tory and immune responses, To explore the role of IL-13 in bone metabo lism, we examined the effects of the cytokine on bone resorption and P G synthesis in osteoblasts, IL-13 suppressed the bone-resorbing activi ty stimulated by IL-1 alpha, which was determined by the release of Ca -45 from prelabeled mouse long bones. Histologic examinations revealed that IL-1 alpha markedly stimulated bone resorption with increased os teoclast recruitment, and that the simultaneous addition of IL-13 cons iderably inhibited it, The gamma-chain of IL-2 receptors may be functi onally involved in the signal transduction of not only IL-2, but also IL-4, IL-7, and IL-13, Of these cytokines, IL-4 similarly suppressed I L-1 alpha-induced bone resorption, but IL-2 and IL-7 did not, Both IL- 13 and IL-4 inhibited PGE(2) production stimulated by IL-1 alpha in lo ng bone cultures, Suppression of IL-1 alpha-induced bone resorption by IL-13 and IL-4 was recovered by adding exogenous PCE(2) to the long b one cultures, Neither IL-4 nor IL-13 further inhibited IL-1 alpha-indu ced bone resorption in the presence of indomethacin. To examine the ef fects of IL-13 on PG synthesis, we measured the mRNA levels of cytosol ic phospholipase A(2) (cPLA(2)), constitutively expressed cyclooxygena se (COX-1) and inducible COX (COX-2) in mouse osteoblast-like cells, I L-1 alpha markedly stimulated the mRNA expression of COX-2, but not th at of COX-1, Both IL-13 and IL-4 dose-dependently suppressed the IL-1 alpha-induced stimulation of both COX-2 mRNA expression and PGE(2) syn thesis, A small increase (1.7-fold) in cPLA(2) mRNA levels was detecte d in the cultures with IL-1 alpha, but the expression was not affected by IL-13 or IL-4, These results indicated that IL-13 and IL-4 inhibit bone resorption by suppressing COX-2-dependent PG synthesis in osteob lasts.