T-cells mediate an inhibitory effect of interleukin-4 on osteoclastogenesis

Mirosavljevic, Danijela, Quinn, Julian M W, Elliott, Jan, Horwood, Nicole J ORCID: https://orcid.org/0000-0002-6344-1677, Martin, T John and Gillespie, Matthew T (2003) T-cells mediate an inhibitory effect of interleukin-4 on osteoclastogenesis. Journal of Bone and Mineral Research, 18 (6). pp. 984-993. ISSN 0884-0431

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Abstract

IL-4 is an important cytokine that can influence bone. We identified two distinct actions of IL-4 to inhibit osteoclast formation: one direct on osteoclast progenitors and the second through the production of a novel T-cell surface-associated molecule(s). These data show a new link between the immune system and bone. The Th2 cytokine interleukin (IL)-4 inhibits osteoclast formation in vitro but also acts on other cell types found in bone, including T-cells and macrophages. Because some osteoclastogenesis inhibitors (e.g., IL-12) act indirectly through T-cells, we investigated IL-4 action on osteoclastogenesis in the presence of T-cells. Osteoclast formation from murine spleen cells treated with RANKL and macrophage colony-stimulating factor (M-CSF) was blocked by IL-4 even when spleen cells were depleted of T-cells (Thy 1.2+) and/or B-cells (B220+). Also, IL-4 inhibited osteoclastogenesis in RANKL/M-CSF-stimulated adherent spleen cells, Rag1 -/- (lymphocyte-deficient) spleen cells, and bone marrow macrophages, indicating an action on myelomonocytic cells to block osteoclastogenesis. In contrast, IL-4 did not inhibit osteoclastogenesis in cells from IL-4 receptor null mice (IL-4R -/-). However, when wildtype T-cells were added to IL-4R -/- spleen cell cultures, IL-4 inhibited osteoclast formation, indicating a T-cell-dependent action. Osteoclast formation in RANKL-stimulated RAW 264.7 cells was not inhibited by IL-4 unless T-cells were added to the culture. Separation of RAW 264.7 cells and T-cells by semipermeable membrane ablated this action of IL-4, suggesting the induction of a membrane-associated osteoclastogenesis inhibitor. However, membrane-bound inhibitors thymic shared antigen-1 (TSA-1) and osteoclast inhibitory lectin (OCIL) were not regulated by IL-4. In summary, at least two mechanisms of IL-4 -mediated osteoclastogenesis inhibition exist, including a direct action on myelomonocytic progenitors (from which osteoclasts derive) and an indirect action through T-cells that may involve novel anti-osteoclastic factors.

Item Type:	Article
Uncontrolled Keywords:	animals,base sequence,pharmacology,cell line,dna primers,deficiency,lymphocyte depletion,pharmacology,male,pharmacology,mice,mice, inbred c57bl,mice, knockout,drug effects,rank ligand,receptor activator of nuclear factor-kappa b,reverse transcriptase polymerase chain reaction,drug effects,drug effects,immunology
Faculty \ School:	Faculty of Medicine and Health Sciences > Norwich Medical School
UEA Research Groups:	Faculty of Medicine and Health Sciences > Research Centres > Metabolic Health
Depositing User:	LivePure Connector
Date Deposited:	06 Mar 2019 11:30
Last Modified:	19 Oct 2023 02:23
URI:	https://ueaeprints.uea.ac.uk/id/eprint/70143
DOI:	10.1359/jbmr.2003.18.6.984

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