Interleukin-4 as a potent inhibitor of bone resorption

Watanabe, Kenichi; Tanaka, Yoshiya; Morimoto, Isao; Yahata, Katsuya; Zeki, Kazuya; Fujihira, Takashi; Yamashita, Uki; Eto, Sumiya

doi:10.1016/0006-291x(90)91550-c

Cited by 106 publications

(49 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Consistent with this observation, ovariectomy or parathyroid hormone-related proteinstimulated bone resorption is blunted by IL-4 in vivo (14,35). The cytokine also decreases isotope release from 45 Ca-labeled fetal mouse long bones exposed osteoclastogenic factors (13). Finally, IL-4 decreases formation of osteoclasts from cultured marrow (15,21).…”

Section: Interleukin-4 and Osteoclastogenesissupporting

confidence: 61%

“…The hematopoietic origin of osteoclasts has led to the hypothesis that IL-4 may play an important role in the regulation of bone metabolism. Indeed, IL-4 inhibits the in vitro bone resorption stimulated by various agents, and the inhibitory effect of IL-4 on bone resorption is abolished by a monoclonal anti-IL-4 antibody (13). IL-4 also inhibits spontaneous and parathyroid hormone-related protein-stimulated osteoclast formation and modulates development of humoral hypercalcemia malignancy in intact mice (14).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Interleukin-4 Reversibly Inhibits Osteoclastogenesis via Inhibition of NF-κB and Mitogen-activated Protein Kinase Signaling

Shi

Wang

Teitelbaum

et al. 2002

Journal of Biological Chemistry

192

141

View full text Add to dashboard Cite

To define the molecular mechanism(s) by which interleukin (IL)-4 reversibly inhibits formation of osteoclasts (OCs) from bone marrow macrophages (BMMs), we examined the capacity of this T cell-derived cytokine to impact signals known to modulate osteoclastogenesis, which include those initiated by macrophage colonystimulating factor (M-CSF), receptor for activation of NF-B ligand (RANKL), tumor necrosis factor (TNF), and IL-1. We find that although pretreatment of BMMs with IL-4 does not alter M-CSF signaling, it reversibly blocks RANKL-dependent activation of the NF-B, JNK, p38, and ERK signals. IL-4 also selectively inhibits TNF signaling, while enhancing that of IL-1. Contrary to previous reports, we find that MEK inhibitors dose-dependently inhibit OC differentiation. To identify more proximal signals mediating inhibition of OC formation by IL-4, we used mice lacking STAT6 or SHIP1, two adapter proteins that bind the IL-4 receptor. IL-4 fails to inhibit RANKL/M-CSF-induced osteoclastogenesis by BMMs derived from STAT6-, but not SHIP1-, knockout mice. Consistent with this observation, the inhibitory effects of IL-4 on RANKL-induced NF-B and mitogen-activated protein kinase activation are STAT6-dependent. We conclude that IL-4 reversibly arrests osteoclastogenesis in a STAT6-dependent manner by 1) preventing IB phosphorylation and thus NF-B activation, and 2) blockade of the JNK, p38, and ERK mitogen-activated protein kinase pathways.

show abstract

Section: Interleukin-4 and Osteoclastogenesissupporting

confidence: 61%

mentioning

confidence: 99%

Interleukin-4 Reversibly Inhibits Osteoclastogenesis via Inhibition of NF-κB and Mitogen-activated Protein Kinase Signaling

Shi

Wang

Teitelbaum

et al. 2002

Journal of Biological Chemistry

192

141

View full text Add to dashboard Cite

show abstract

“…Other authors have found a lack of response of TNF-to IL-1 , PTH and 1,25(OH) 2 D 3 (Gowen et al 1990) suggesting that it is not the primary cytokine by which osteotrophic hormones mediate bone resorption. Similarly, IL-3, GM-CSF and IL-4, which are known to be produced by osteoblasts (Lorenzo et al 1987, Felix et al 1988, Watanabe et al 1990) and play a part in bone turnover, do not appear to be regulated by T3.…”

Section: Discussionmentioning

confidence: 99%

Tri-iodothyronine regulates the production of interleukin-6 and interleukin-8 in human bone marrow stromal and osteoblast-like cells

Siddiqi

Burrin²,

Wood³

et al. 1998

Journal of Endocrinology

View full text Add to dashboard Cite

Hyperthyroidism is associated with increased bone resorption but the mechanisms by which thyroid hormone (T3) affects bone cell metabolism remain unclear. Recently it has been suggested that T3 stimulates osteoclastic resorption indirectly through the release of soluble mediators from osteoblasts. The aim of the present study was to investigate whether the T3-induced increase in bone resorption could be due to the regulation of cytokine production by human osteoblasts (hOb).The effects of T3 (1, 10, 100 nM) and IL-1 (100 U/ml) as the positive control were examined on cytokine protein release and mRNA levels in cultured hOb cell lines (MG63, SaOs-2), primary hOb and human bone marrow stromal (hBMS) cells. T3 increased IL-6 and IL-8 mRNA levels as well as IL-6 and IL-8 protein release into the culture media from MG63 and hBMS cells in a time-and dose-dependent manner. The maximal effect on protein release in hBMS cells occurred at 24 h with a dose of T3 10 nM (IL-6 5·5 1·1-fold above controls; IL-8 3·7 0·5-fold above controls, P<0·05). At the same time, mRNA levels in hBMS cells were increased 6·2 0·8-fold for IL-6 (P<0·05) and 5·7 0·8-fold for IL-8 (P<0·05). Similar results were obtained in MG63 cells but no response was seen in SaOs-2 or hOb cells despite measurable basal production. Nor was there detectable regulation of IL-1 , IL-3, IL-11, IL-4 or granulocyte macrophage-colony stimulating factor by T3 in any cell type.In conclusion, T3 increases IL-6 and IL-8 production by MG63 and hBMS cells, suggesting that IL-6 and IL-8 may be T3-regulated genes in osteoblasts.

show abstract

“…The mice were immunized intradermally at the base of the tail with 100 µL of emulsion (100 µg of collagen). On day 21, mice were given an intraperitoneal booster injection of 100 µg of type II collagen dissolved in PBS, and normally arthritis onset will then occur around days [25][26][27][28].…”

Section: Methodsmentioning

confidence: 99%

“…This lack of IL-4 may contribute to the uneven balance between destructive and regulatory mediators in the synovium of the RA process. In vitro, IL-4 has been shown to be an inhibitor of bone resorption (28)(29)(30)(31) and osteoclast-like cell formation (32,33); however, its role in vivo has not been identified.…”

mentioning

confidence: 99%

IL-4 gene therapy for collagen arthritis suppresses synovial IL-17 and osteoprotegerin ligand and prevents bone erosion

Lubberts¹,

Joosten²,

Chabaud³

et al. 2000

J. Clin. Invest.

279

204

View full text Add to dashboard Cite

Interleukin-4 as a potent inhibitor of bone resorption

Cited by 106 publications

References 23 publications

Interleukin-4 Reversibly Inhibits Osteoclastogenesis via Inhibition of NF-κB and Mitogen-activated Protein Kinase Signaling

Interleukin-4 Reversibly Inhibits Osteoclastogenesis via Inhibition of NF-κB and Mitogen-activated Protein Kinase Signaling

Tri-iodothyronine regulates the production of interleukin-6 and interleukin-8 in human bone marrow stromal and osteoblast-like cells

IL-4 gene therapy for collagen arthritis suppresses synovial IL-17 and osteoprotegerin ligand and prevents bone erosion

Contact Info

Product

Resources

About