Interleukin-33 is expressed in differentiated osteoblasts and blocks osteoclast formation from bone marrow precursor cells

Abstract

Since the hematopoetic system is located within the bone marrow, it is not surprising that recent evidence has demonstrated the existence of molecular interactions between bone and immune cells. While interleukin 1 (IL-1) and IL-18, two cytokines of the IL-1 family, have been shown to regulate differentiation and activity of bone cells, the role of IL-33, another IL-1 family member, has not been addressed yet. Since we observed that the expression of IL-33 increases during osteoblast differentiation, we analyzed its possible influence on bone formation and observed that IL-33 did not affect matrix mineralization but enhanced the expression of Tnfsf11, the gene encoding RANKL. This finding led us to analyze the skeletal phenotype of Il1rl1-deficient mice, which lack the IL-33 receptor ST2. Unexpectedly, these mice displayed normal bone formation but increased bone resorption, thereby resulting in low trabecular bone mass. Since this finding suggested a negative influence of IL-33 on osteoclastogenesis, we next analyzed osteoclast differentiation from bone marrow precursor cells and observed that IL-33 completely abolished the generation of TRACP þ multinucleated osteoclasts, even in the presence of RANKL and macrophage colony-stimulating factor (M-CSF). Although our molecular studies revealed that IL-33 treatment of bone marrow cells caused a shift toward other hematopoetic lineages, we further observed a direct negative influence of IL-33 on the osteoclastogenic differentiation of RAW264.7 macrophages, where IL-33 repressed the expression of Nfatc1, which encodes one of the key transciption factors of osteoclast differentiation. Taken together, these findings have uncovered a previously unknown function of IL-33 as an inhibitor of bone resorption. ß

Effects of inflammatory and anti‐inflammatory cytokines on the bone

“…In contrast, another IL-1 family member, IL-18, blocks bone resorption by inducing the expression of GM-CSF, which is a differentiation factor for dendritic cells rather than osteoclasts [38]. Finally, IL-33, which is involved in the polarization of TH2 lymphocytes, activation of basophils, mast cells, eosinophils and chemoattraction of neutrophils to inflammatory sites, is a potent suppressor of osteoclast activation [39,40]. Interleukin-33 promotes the differentiation of mononuclear cells to dendritic cells and alternativelyEuropean Journal of Clinical Investigation Vol 41 1363 activated macrophages, thereby reducing the pool of osteoclast precursors and impairing osteoclastogenesis [40].…”

“…Finally, IL-33, which is involved in the polarization of TH2 lymphocytes, activation of basophils, mast cells, eosinophils and chemoattraction of neutrophils to inflammatory sites, is a potent suppressor of osteoclast activation [39,40]. Interleukin-33 promotes the differentiation of mononuclear cells to dendritic cells and alternativelyEuropean Journal of Clinical Investigation Vol 41 1363 activated macrophages, thereby reducing the pool of osteoclast precursors and impairing osteoclastogenesis [40]. Importantly, this effect is accompanied by the expression of IL-4 and GMCSF by mononuclear cells, which are inhibitors of osteoclast differentiation.…”

BCR-ABL–Induced Deregulation of the IL-33/ST2 Pathway in CD34(+) Progenitors from Chronic Myeloid Leukemia Patients

“…Since its first description, important roles have been ascribed to IL-33, both as a conventional cytokine and as an alarmin, implicated in a number of pathologies (8,9). Knowing that endothelial cells and osteoblasts (9,10), two components of the hematopoietic stem cell niche, are the main sources of IL-33, while several immune/hematopoietic cells, including primary progenitors (11), constitute its natural targets, we hypothesized that IL-33 might enhance proliferation and/or mediate imatinib mesylate resistance in CML CD34(þ) cells. We found that the IL-33 receptor ST2 was constitutively expressed and was functional in leukemic CD34(þ) cells because it mediated the proliferation and cytokine production induced by IL-33, whereas CD34(þ) cells from healthy donors (HD) neither expressed ST2 nor responded to IL-33.…”

Severe Neutrophil-Dominated Inflammation and Enhanced Myelopoiesis in IL-33–Overexpressing CMV/IL33 Mice

“…In the mouse, an excess of IL-33 activity, caused by systemic or local injection of the recombinant protein (8,(14)(15)(16)(17)(18)(19)(20)(21) by ubiquitous or tissue-specific transgenic overexpression (22,23), or by increased release of the endogenous protein because of removal of its nuclear localization domain (24), was linked to enhanced eosinophil accumulation, eosinophilic organ infiltration, inflammation (8,14,18,(22)(23)(24), basophil expansion (15), or recruitment and activation of neutrophils (16,17,(19)(20)(21). The addition of recombinant IL-33 to cultured mouse bone marrow (BM) cells in different experimental settings promoted cell viability, proliferation, production of myeloid growth factors, and/or modulated cell differentiation (14,15,(25)(26)(27)(28)(29). Furthermore, ST2 expression was described on human and mouse hematopoietic precursor cells, suggesting that IL-33 might exert direct effects on hematopoietic progenitors (30,31).…”