Limits...
Regulatory effect of calcineurin inhibitor, tacrolimus, on IL-6/sIL-6R-mediated RANKL expression through JAK2-STAT3-SOCS3 signaling pathway in fibroblast-like synoviocytes.

Choe JY, Park KY, Park SH, Lee SI, Kim SK - Arthritis Res. Ther. (2013)

Bottom Line: The effects of tacrolimus on synovial inflammation and bone erosion were assessed using mice with arthritis induced by K/BxN serum.The tartrate-resistant acid phosphatase staining assay was performed to assess the effect of tacrolimus on osteoclast differentiation.Among negative regulators of the JAK/STAT pathway, such as CIS1, SOCS1, and SOCS3, only SOCS3 is significantly induced by tacrolimus.

View Article: PubMed Central - HTML - PubMed

ABSTRACT

Introduction: This study investigated whether the calcineurin inhibitor, tacrolimus, suppresses receptor activator of NF-κB ligand (RANKL) expression in fibroblast-like synoviocytes (FLS) through regulation of IL-6/Janus activated kinase (JAK2)/signal transducer and activator of transcription-3 (STAT3) and suppressor of cytokine signaling (SOCS3) signaling.

Methods: The expression of RANKL, JAK2, STAT3, and SOCS3 proteins was assessed by western blot analysis, real-time PCR and ELISA in IL-6 combined with soluble IL-6 receptor (sIL-6R)-stimulated rheumatoid arthritis (RA)-FLS with or without tacrolimus treatment. The effects of tacrolimus on synovial inflammation and bone erosion were assessed using mice with arthritis induced by K/BxN serum. Immunofluorescent staining was performed to identify the effect of tacrolimus on RANKL and SOCS3. The tartrate-resistant acid phosphatase staining assay was performed to assess the effect of tacrolimus on osteoclast differentiation.

Results: We found that RANKL expression in RA FLS is regulated by the IL-6/sIL-6R/JAK2/STAT3/SOCS3 pathway. Inhibitory effects of tacrolimus on RANKL expression in a serum-induced arthritis mice model were identified. Tacrolimus inhibits RANKL expression in IL-6/sIL-6R-stimulated FLS by suppressing STAT3. Among negative regulators of the JAK/STAT pathway, such as CIS1, SOCS1, and SOCS3, only SOCS3 is significantly induced by tacrolimus. As compared to dexamethasone and methotrexate, tacrolimus more potently suppresses RANKL expression in FLS. By up-regulating SOCS3, tacrolimus down-regulates activation of the JAK-STAT pathway by IL-6/sIL-6R trans-signaling, thus decreasing RANKL expression in FLS.

Conclusions: These data suggest that tacrolimus might affect the RANKL expression in IL-6 stimulated FLS through STAT3 suppression, together with up-regulation of SOCS3.

Show MeSH

Related in: MedlinePlus

Summary for the effect of calcineurin inhibitor, tacrolimus, on the regulation of RANKL expression through IL-6/sIL-6R/JAK2/STAT3/SOCS3 pathway. IL-6, interleukin-6; JAK2, Janus activated kinase; RANKL, receptor activator of NF-κB ligand; sIL-6R, soluble interleukin-6 receptor; SOCS3, suppressor of cytokine signaling 3; STAT3, signal transducer and activator of transcription 3.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3672788&req=5

Figure 6: Summary for the effect of calcineurin inhibitor, tacrolimus, on the regulation of RANKL expression through IL-6/sIL-6R/JAK2/STAT3/SOCS3 pathway. IL-6, interleukin-6; JAK2, Janus activated kinase; RANKL, receptor activator of NF-κB ligand; sIL-6R, soluble interleukin-6 receptor; SOCS3, suppressor of cytokine signaling 3; STAT3, signal transducer and activator of transcription 3.

Mentions: In summary, the cytokine IL-6, together with sIL-6R, has a pathogenic role in the development of RA through its effects on synovial inflammation and bone destruction. As such, it is considered a promising therapeutic target molecule. The intimate interaction between synoviocytes and osteoclasts contributes to the development of bone erosion. RANKL has an essential role in the regulation of osteoclast activation and differentiation. Our study showed that FLS is another source of RANKL production in synovial inflammation seen in RA. In addition, we found that RANKL expression by RA FLS depends on the JAK2-STAT3-SOCS3 signaling pathway at both the mRNA and protein levels. As shown in Figure 6, taken together these results indicate that tacrolimus has an inhibitory effect on RANKL expression in RA synoviocytes in both in vivo and in vitro experiments through its regulation of the JAK2-STAT3-SOCS3 pathway.


Regulatory effect of calcineurin inhibitor, tacrolimus, on IL-6/sIL-6R-mediated RANKL expression through JAK2-STAT3-SOCS3 signaling pathway in fibroblast-like synoviocytes.

Choe JY, Park KY, Park SH, Lee SI, Kim SK - Arthritis Res. Ther. (2013)

Summary for the effect of calcineurin inhibitor, tacrolimus, on the regulation of RANKL expression through IL-6/sIL-6R/JAK2/STAT3/SOCS3 pathway. IL-6, interleukin-6; JAK2, Janus activated kinase; RANKL, receptor activator of NF-κB ligand; sIL-6R, soluble interleukin-6 receptor; SOCS3, suppressor of cytokine signaling 3; STAT3, signal transducer and activator of transcription 3.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3672788&req=5

Figure 6: Summary for the effect of calcineurin inhibitor, tacrolimus, on the regulation of RANKL expression through IL-6/sIL-6R/JAK2/STAT3/SOCS3 pathway. IL-6, interleukin-6; JAK2, Janus activated kinase; RANKL, receptor activator of NF-κB ligand; sIL-6R, soluble interleukin-6 receptor; SOCS3, suppressor of cytokine signaling 3; STAT3, signal transducer and activator of transcription 3.
Mentions: In summary, the cytokine IL-6, together with sIL-6R, has a pathogenic role in the development of RA through its effects on synovial inflammation and bone destruction. As such, it is considered a promising therapeutic target molecule. The intimate interaction between synoviocytes and osteoclasts contributes to the development of bone erosion. RANKL has an essential role in the regulation of osteoclast activation and differentiation. Our study showed that FLS is another source of RANKL production in synovial inflammation seen in RA. In addition, we found that RANKL expression by RA FLS depends on the JAK2-STAT3-SOCS3 signaling pathway at both the mRNA and protein levels. As shown in Figure 6, taken together these results indicate that tacrolimus has an inhibitory effect on RANKL expression in RA synoviocytes in both in vivo and in vitro experiments through its regulation of the JAK2-STAT3-SOCS3 pathway.

Bottom Line: The effects of tacrolimus on synovial inflammation and bone erosion were assessed using mice with arthritis induced by K/BxN serum.The tartrate-resistant acid phosphatase staining assay was performed to assess the effect of tacrolimus on osteoclast differentiation.Among negative regulators of the JAK/STAT pathway, such as CIS1, SOCS1, and SOCS3, only SOCS3 is significantly induced by tacrolimus.

View Article: PubMed Central - HTML - PubMed

ABSTRACT

Introduction: This study investigated whether the calcineurin inhibitor, tacrolimus, suppresses receptor activator of NF-κB ligand (RANKL) expression in fibroblast-like synoviocytes (FLS) through regulation of IL-6/Janus activated kinase (JAK2)/signal transducer and activator of transcription-3 (STAT3) and suppressor of cytokine signaling (SOCS3) signaling.

Methods: The expression of RANKL, JAK2, STAT3, and SOCS3 proteins was assessed by western blot analysis, real-time PCR and ELISA in IL-6 combined with soluble IL-6 receptor (sIL-6R)-stimulated rheumatoid arthritis (RA)-FLS with or without tacrolimus treatment. The effects of tacrolimus on synovial inflammation and bone erosion were assessed using mice with arthritis induced by K/BxN serum. Immunofluorescent staining was performed to identify the effect of tacrolimus on RANKL and SOCS3. The tartrate-resistant acid phosphatase staining assay was performed to assess the effect of tacrolimus on osteoclast differentiation.

Results: We found that RANKL expression in RA FLS is regulated by the IL-6/sIL-6R/JAK2/STAT3/SOCS3 pathway. Inhibitory effects of tacrolimus on RANKL expression in a serum-induced arthritis mice model were identified. Tacrolimus inhibits RANKL expression in IL-6/sIL-6R-stimulated FLS by suppressing STAT3. Among negative regulators of the JAK/STAT pathway, such as CIS1, SOCS1, and SOCS3, only SOCS3 is significantly induced by tacrolimus. As compared to dexamethasone and methotrexate, tacrolimus more potently suppresses RANKL expression in FLS. By up-regulating SOCS3, tacrolimus down-regulates activation of the JAK-STAT pathway by IL-6/sIL-6R trans-signaling, thus decreasing RANKL expression in FLS.

Conclusions: These data suggest that tacrolimus might affect the RANKL expression in IL-6 stimulated FLS through STAT3 suppression, together with up-regulation of SOCS3.

Show MeSH
Related in: MedlinePlus