IL-23 induces receptor activator of NF-kappaB ligand expression in fibroblast-like synoviocytes via STAT3 and NF-kappaB signal pathways.

Abstract

Interleukin (IL)-23 stimulates T lymphocytes to produce inflammatory molecules, which can cause inflammatory arthritis. This study was undertaken to explore the role of IL-23 in stimulating the expression of the receptor activator of the nuclear factor kappa B (NF-kappaB) ligand (RANKL) and osteoclastogenic activity in human fibroblast-like synoviocytes (FLS). These cells were separated from the synovium of patients with rheumatoid arthritis (RA-FLS) and osteoarthritis (OA-FLS) and stimulated with IL-23. RANKL expression was measured by real-time polymerase chain reaction (PCR) amplification and immunostaining. Osteoclast precursor cells were cocultured with IL-23-stimulated RA-FLS and OA-FLS and subsequently stained for tartrate-resistant acid phosphatase (TRAP) activity. IL-23 upregulated RANKL expression in RA-FLS. The expression of RANKL mRNA and protein was blocked completely by inhibitors of NF-kappaB (parthenolide) or of the JAK II-STAT3 pathway (AG490), showing that the RANKL expression pathway is mediated by NF-kappaB and STAT3. TRAP-positive osteoclastogenesis was enhanced in IL-23-stimulated FLS. RA-FLS were more responsive to IL-23 in terms of their RANKL expression than OA-FLS or normal FLS. Thus, IL-23 appears to induce joint inflammation and bone destruction by stimulating RANKL expression in RA-FLS. These interactions between IL-23 and FLS indicate possible new therapeutic approaches for treating bone destruction in patients with inflammatory diseases.

• Authors: Xia Li, Kyoung-Woon Kim, Mi-La Cho, Ji-Hyeon Ju, Chang-Min Kang, Hye-Joa Oh, Jun-Ki Min, Sang-Heon Lee, Sung-Hwan Park, Ho-Youn Kim
• Journal: Immunology letters (Immunol Lett) Vol. 127 Issue 2 Pg. 100-7 (Jan 04 2010) ISSN: 1879-0542 [Electronic] Netherlands
• PMID: 19900478 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Interleukin-23
• NF-kappa B
• RANK Ligand
• STAT3 Transcription Factor
• Sesquiterpenes
• Tyrphostins
• alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide
• parthenolide

Topics

• Adult
• Aged
• Arthritis, Rheumatoid (immunology)
• Cell Differentiation (drug effects)
• Female
• Fibroblasts (drug effects, immunology, metabolism, pathology)
• Gene Expression Regulation (drug effects)
• Humans
• Interleukin-23 (metabolism, pharmacology)
• Male
• Middle Aged
• NF-kappa B (antagonists & inhibitors, metabolism)
• Osteoarthritis (immunology)
• Osteoclasts (drug effects, immunology, metabolism, pathology)
• RANK Ligand (genetics, immunology, metabolism)
• STAT3 Transcription Factor (antagonists & inhibitors, metabolism)
• Sesquiterpenes (pharmacology)
• Signal Transduction (immunology)
• Synovial Membrane (pathology)
• Tyrphostins (pharmacology)