Delayed onset and reduced severity of collagen-induced arthritis in interleukin-6-deficient mice

Sasai, Mitsuko; Saeki, Yukihiko; Ohshima, Shiro; Nishioka, K; Mima, Toru; Tanaka, Toshio; Katada, Yoshinori; Yoshizaki, Kazuyuki; Suemura, Masaki; Kishimoto, Tadamitsu

doi:10.1002/1529-0131(199908)42:8<1635::aid-anr11>3.0.co;2-q

Cited by 198 publications

(116 citation statements)

References 40 publications

Supporting

Mentioning

109

Contrasting

Unclassified

Order By: Relevance

“…IL-21 has been reported to promote production of IL-17 from activated human T cells (41).Thus, blockade of IL-21 in CIA may function, in part, by modulation of IL-6-driven inflammation, either directly or through down-regulation of TNF␣ or IL-17. IL-6 has a pathogenic role in CIA (26,31,42) and is a critical inflammatory cytokine in RA. Blockade of IL-6R has demonstrated efficacy in clinical trials of RA (43).…”

Section: Discussionmentioning

confidence: 99%

Blockade of the interleukin‐21/interleukin‐21 receptor pathway ameliorates disease in animal models of rheumatoid arthritis

Young¹,

Hegen²,

Margery³

et al. 2007

Arthritis & Rheumatism

256

203

View full text Add to dashboard Cite

Objective. Interleukin-21 (IL-21) is a T cellderived cytokine that modulates T cell, B cell, and natural killer cell responses. In this study, the effects of blocking IL-21 were examined in 2 rodent models of rheumatoid arthritis (RA) to determine whether IL-21 contributes to their pathologic processes.Methods. DBA/1 mice were immunized with bovine type II collagen and then treated with murine IL-21 receptor Fc fusion protein (IL-21R.Fc), which was initiated after the onset of arthritis symptoms in 10% of the cohort. The mice were assessed 3 times per week for signs of disease, including histologic features as well as serum cytokine, Ig, and cytokine messenger RNA (mRNA) levels in the paws. In a separate experiment, Lewis rats were immunized with Freund's complete adjuvant followed by administration of IL-21R.Fc at the peak of inflammation in the joints. Rats were assessed daily for histologic features and for scoring of arthritis severity. In addition, the effects of IL-21R.Fc on the production of interferon-␥ (IFN␥) by T cells were examined.Results Conclusion. These findings demonstrate a pathogenic role for IL-21 in animal models of RA, and support consideration of IL-21 as a therapeutic target in human RA.

show abstract

Section: Discussionmentioning

confidence: 99%

Blockade of the interleukin‐21/interleukin‐21 receptor pathway ameliorates disease in animal models of rheumatoid arthritis

Young¹,

Hegen²,

Margery³

et al. 2007

Arthritis & Rheumatism

256

203

View full text Add to dashboard Cite

show abstract

“…IL-6 has also been shown to contribute to joint inflammation and an anti-IL-6 therapy with an anti-IL-6 receptor mAb (MRA) ameliorates RA (18). Furthermore, IL-6 Ϫ/Ϫ mice show protection against disease in the CIA model (19,20). Interestingly, double deletion of TNFR1 and IL-6 showed a synergistic protective effect in CIA (21).…”

Section: Discussionmentioning

confidence: 99%

MAPKAP Kinase 2-Deficient Mice Are Resistant to Collagen-Induced Arthritis

Hegen

Gaestel

Nickerson‐Nutter

et al. 2006

The Journal of Immunology

138

107

View full text Add to dashboard Cite

TNF-α is a pleiotropic cytokine considered a primary mediator of immune regulation and inflammatory response and has been shown to play a central role in rheumatoid arthritis (RA). MAPKAP kinase 2 (MK2) is a serine/threonine kinase that is regulated through direct phosphorylation by p38 MAPK, and has been shown to be an essential component in the inflammatory response that regulates the biosynthesis of TNF-α at a posttranscriptional level. The murine model of collagen-induced arthritis (CIA) is an established disease model to study pathogenic mechanisms relevant to RA. In this study, we report that deletion of the MK2 gene in DBA/1LacJ mice confers protection against CIA. Interestingly, the MK2 heterozygous mutants display an intermediate level of protection when compared with homozygous mutant and wild-type littermates. We show that MK2−/− and MK2+/− mice exhibit decreased disease incidence and severity in the CIA disease model and reduced TNF-α and IL-6 serum levels following LPS/d-Gal treatment compared with wild-type mice. Additionally, we show that levels of IL-6 mRNA in paws of mice with CIA correlate with the disease status. These findings suggest that an MK2 inhibitor could be of great therapeutic value to treat inflammatory diseases like RA.

show abstract

“…In IL-6-knockout mice, CIA was less severe and had a delayed onset compared with CIA in wild-type mice (104). Similarly, injection with methylated bovine serum albumin induced AIA in wildtype mice but failed to induce joint swelling in IL-6-knockout mice (105).…”

Section: From Animal Models Toward the Clinicmentioning

confidence: 92%

Evaluation of therapeutic targets in animal models of arthritis: How does it relate to rheumatoid arthritis?

Bevaart¹,

Vervoordeldonk²,

Tak³

2010

Arthritis & Rheumatism

232

193

View full text Add to dashboard Cite

There are accumulating data describing the association between diabetes and cancer mortality from Westernised populations. There are no data describing the relationship between diabetes and cancer mortality in African or South Asian populations from developing countries. We explored the relationship of abnormal glucose tolerance and diabetes on cancer mortality risk in a large, multi‐ethnic cohort from the developing nation of Mauritius. Population‐based surveys were undertaken in 1987, 1992 and 1998. The 9559 participants comprised 66% of South Asian (Indian), 27% of African (Creole), and 7% of Chinese descent. Cox's proportional hazards model with time varying covariates was used to obtain hazard ratios (HRs) and 95% confidence intervals (95% CI) for risk of cancer mortality, after adjustment for confounding factors. In men, but not women, cancer mortality risk increased with rising 2h‐PG levels with HR for the top versus bottom quintile of 2.77 (95%CI: 1.28 to 5.98). South Asian men with known diabetes had a significantly greater risk of cancer mortality than those with normal glucose tolerance (NGT) HR: 2.74 (95%CI: 1.00‐7.56). Overall, impaired glucose tolerance was associated with an elevated risk of cancer mortality compared to NGT (HR: 1.47, 95% CI: 0.98–2.19), though this was not significant. We have shown that the association between abnormal glucose tolerance and cancer extends to those of African and South Asian descent. These results highlight the importance of understanding this relationship in a global context to direct future health policy given the rapid increase in type 2 diabetes, especially in developing nations.

show abstract

Delayed onset and reduced severity of collagen-induced arthritis in interleukin-6-deficient mice

Cited by 198 publications

References 40 publications

Blockade of the interleukin‐21/interleukin‐21 receptor pathway ameliorates disease in animal models of rheumatoid arthritis

Blockade of the interleukin‐21/interleukin‐21 receptor pathway ameliorates disease in animal models of rheumatoid arthritis

MAPKAP Kinase 2-Deficient Mice Are Resistant to Collagen-Induced Arthritis

Evaluation of therapeutic targets in animal models of arthritis: How does it relate to rheumatoid arthritis?

Contact Info

Product

Resources

About