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Cited by 202Bone Metabolism and DiseasesCytokine Signaling Pathways and InteractionsRheumatoid Arthritis Research and Therapies

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

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Wei, Shi, Wang, Michael W.-H., Teitelbaum, Steven L., Ross, F. Patrick·2002·Journal of Biological Chemistry
DOI 10.1074/jbc.m104957200
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Abstract

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 colony-stimulating factor (M-CSF), receptor for activation of NF-kappa 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-kappa 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-kappa 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 I kappa B phosphorylation and thus NF-kappa B activation, and 2) blockade of the JNK, p38, and ERK mitogen-activated protein kinase pathways.

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  • IL-4 inhibits osteoclastogenesis by blocking the JNK, p38, and ERK protein kinase pathways, which are upstream of NFATc1.

    “Wei and associates found that IL-4 inhibited osteoclastogenesis by blocking the JNK, p38, and ERK protein kinase pathways, which are upstream of NFATc1 [40].”

    From Osteoclasts and Microgravity (2020) · cites this paper as [40]

    The Abstract and Discussion report that IL-4 inhibits osteoclastogenesis and, after prolonged treatment, blocks RANKL-induced JNK, p38, and ERK activation. The cited paper does not identify these pathways as upstream of NFATc1; a search for NFATc1 found no passage establishing that relationship. (LLM, conf=0.88)

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  1. Yasuda, H., Shima, N., Nakagawa, N., Yamaguchi, K., Kinosaki, M., Mochizuki, S., Tomoyasu, A., Yano, K., Goto, M., Murakami, A., Tsuda, E., Morinaga, T., Higashio, K., Udagawa, N., Takahashi, N., and Suda, T. (1998) Proc. Natl. Acad. Sci. U. S. A. 95, 3597-3602
  2. Lewis, D. B., Liggitt, H. D., Effmann, E. L., Motley, S. T., Teitelbaum, S. L., Jepsen, K. J., Goldstein, S. A., Bonadio, J., Carpenter, J., and Perlmutter, R. M. (1993) Proc. Natl. Acad. Sci. U. S. A. 90, 11618 -11622
  3. Bendixen, A. C., Shevde, N. K., Dienger, K. M., Willson, T. M., Funk, C. D., and Pike, J. W. (2001) Proc. Natl. Acad. Sci. U. S. A. 98, 2443-2448

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Authors
Wei, S., Wang, M. W.-H., Teitelbaum, S. L., & Ross, F. P.
Affiliations
Washington University in St. Louis (US)
Corresponding author
Ross, F. Patrick
ORCID
Teitelbaum, Steven L.
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
2002-02
Volume
277
Issue
8
Pages
6622-6630
ISSN
0021-9258 (ISSN-L)
DOI
10.1074/jbc.m104957200
OpenAlex
W1998128158
Cited by
202
References
55
Citations by year
2026: 3 · 2025: 3 · 2024: 4 · 2023: 7 · 2022: 4 · 2021: 3 · 2020: 15 · 2019: 3 · 2018: 9 · 2017: 5 · 2016: 7 · 2015: 6 · 2014: 3 · 2013: 10 · 2012: 5
FWCI
5.55
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
  • Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
  • Health Sciences › Medicine › Rheumatology › Rheumatoid Arthritis Research and Therapies
Keywords
IL-4, osteoclastogenesis, NF-κB signaling, mitogen-activated protein kinase, STAT6, SHIP1, RANKL, macrophage colony-stimulating factor, TNF signaling, IL-1 signaling, MEK inhibitors, bone marrow-derived macrophages
MeSH terms
Animals, Bone Marrow Cells, Carrier Proteins, Cells, Cultured, Gene Expression Regulation, Kinetics, Macrophages, Membrane Glycoproteins, Mice, Inbred C57BL, Osteoclasts, Osteogenesis, Signal Transduction, Interleukin-4, Macrophage Colony-Stimulating Factor, NF-kappa B, Cell Culture Techniques, Reverse Transcriptase Polymerase Chain Reaction, MAP Kinase Signaling System, Mice, RANK Ligand, Receptor Activator of Nuclear Factor-kappa B

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