IL-13 and IL-4 inhibit bone resorption by suppressing cyclooxygenase-2-dependent prostaglandin synthesis in osteoblasts.

Abstract

Activated T cells secrete the cytokine IL-13, which regulates inflammatory and immune responses. To explore the role of IL-13 in bone metabolism, we examined the effects of the cytokine on bone resorption and PG synthesis in osteoblasts. IL-13 suppressed the bone-resorbing activity stimulated by IL-1 alpha, which was determined by the release of 45Ca from prelabeled mouse long bones. Histologic examinations revealed that IL-1 alpha markedly stimulated bone resorption with increased osteoclast recruitment, and that the simultaneous addition of IL-13 considerably inhibited it. The gamma-chain of IL-2 receptors may be functionally 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 IL-1 alpha-induced bone resorption, but IL-2 and IL-7 did not. Both IL-13 and IL-4 inhibited PGE2 production stimulated by IL-1 alpha in long bone cultures. Suppression of IL-1 alpha-induced bone resorption by IL-13 and IL-4 was recovered by adding exogenous PGE2 to the long bone cultures. Neither IL-4 nor IL-13 further inhibited IL-1 alpha-induced bone resorption in the presence of indomethacin. To examine the effects of IL-13 on PG synthesis, we measured the mRNA levels of cytosolic phospholipase A2 (cPLA2), constitutively expressed cyclooxygenase (COX-1) and inducible COX (COX-2) in mouse osteoblast-like cells. IL-1 alpha markedly stimulated the mRNA expression of COX-2, but not that 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 PGE2 synthesis. A small increase (1.7-fold) in cPLA2 mRNA levels was detected 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 osteoblasts.

Effects of inflammatory cytokines on bone/cartilage repair

“…It has been a long time since both IL‐4 and IL‐13 have been proved to inhibit bone resorption . The results obtained from subsequent in vivo studies were consistent with this finding .…”

“…71 3.3 | Interleukin-4 and interleukin -13 It has been a long time since both IL-4 and IL-13 have been proved to inhibit bone resorption. 72 The results obtained from subsequent in vivo studies were consistent with this finding. 73 In addition, either IL-4 or IL-13 promotes the formation of ALP in a dose-dependent manner.…”

Trends in Serum Cytokine Expression in Pediatric Skeletal Dysplasia

“…IL‐13 (upregulated in nine cohorts) and IL‐4 (upregulated in the OI and metatropic dysplasia cohorts) are well categorized for their complex roles promoting type II inflammation, but for many years they have also been known to inhibit bone resorption through suppression of prostaglandin synthesis. ( 14 ) IL‐12 (upregulated in nine cohorts) is known to indirectly inhibit osteoblastogenesis. ( 15 ) RANTES (upregulated in eight cohorts) has been identified as a likely factor in the development of osteoarthritis.…”

Transcriptional profiling of canine osteosarcoma identifies prognostic gene expression signatures with translational value for humans

“…M2 macrophages have been associated with poor outcomes in multiple other tumor types [91][92][93] ; however, DOG 2 data suggest that having a greater number of M2 macrophages might be beneficial. The answer might be unique to the bone itself, wherein macrophages and osteoclasts are both derived from monocytes, while IL-4 and IL-13 needed for the differentiation of a monocyte into M2 macrophage are inhibitors of osteoclast formation 94 . Therefore, it is possible that a shift in monocyte differentiation to favor M2 macrophages reduces osteoclast formation and thereby inhibits bone resorption which might be essential to tumor development.…”