Enhanced production of interleukin‐6 in mice with type II collagen–induced arthritis

Takai, Yasuyuki; Seki, Nobuo; Senoh, Hachiro; Yokota, Takashi; Lee, Frank; Hamaoka, Toshiyuki; Fujiwara, Hiromi

doi:10.1002/anr.1780320513

Cited by 69 publications

(24 citation statements)

References 39 publications

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“…In fact, enhanced IL-6 production in synovial tissue, synovial fluid, and serum of RA patients has been reported (5-7). Likewise, enhanced production of IL-6 has been demonstrated in CIA (26). However, there have been some conflicting reports.…”

Section: Discussionmentioning

confidence: 99%

“…T cell clones from rheumatoid synovium can produce large amounts of IFN␥, whereas IL-4 is absent or is present in minimal amounts (32). CIA is also associated with a predominant Th1 profile, especially at the onset of arthritis (26), and Th2 cytokines, such as IL-4 and IL-10, have been demonstrated to have some protective effect against CIA (33)(34)(35). However, it is not clear whether IL-6 can modify the balance between Th1 and Th2 cytokines (36)(37)(38).…”

Section: Discussionmentioning

confidence: 99%

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

Sasai

Saeki

Ohshima

et al. 1999

Arthritis & Rheumatism

198

109

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Objective. To investigate the roles of interleukin-6 (IL-6) in the pathogenesis of rheumatoid arthritis (RA) by studying its effect on murine collagen-induced arthritis (CIA).Methods. IL-6-deficient (IL-6؊/؊) mice with a genetic background of susceptibility to CIA were generated by backcrossing them with DBA/1J mice for 8 generations. Clinical and immunologic features were compared between these mice and IL-6 wild-type (IL-6؉/؉) littermates with CIA.Results. Serum IL-6 levels increased during the development of CIA in IL-6؉/؉ mice. Two prominent peaks were observed. The first was coincident with the onset of arthritis, and the second one was observed during exacerbation of the disease. The onset of arthritis in IL-6؊/؊ mice was delayed for 2 weeks compared with that in IL-6؉/؉ mice, and the severity of arthritis, as indicated by the arthritis score, remained significantly lower in IL-6؊/؊ mice during the entire followup period (14 weeks), although all IL-6؊/؊ mice developed definite arthritis as did the IL-6؉/؉ mice. Histologic severity was also reduced in IL-6؊/؊ mice. In addition, radiologic changes such as osteopenia and bone erosion were reduced significantly in these animals. Both humoral and cellular responses to type II collagen (CII) in IL-6؊/؊ mice were reduced to about half those in IL-6؉/؉ mice. In addition, enhanced production of IL-4 and IL-10 in response to concanavalin A stimulation was observed in IL-6؊/؊ mice.Conclusion. IL-6 plays an important role in the development of CIA, and both suppression of specific immune responses to CII and a tendency to a shift toward a Th2 cytokine profile might contribute in part to the attenuation of CIA in IL-6؊/؊ mice. These findings suggest that blockade of IL-6 might be beneficial in the treatment of RA.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

Sasai

Saeki

Ohshima

et al. 1999

Arthritis & Rheumatism

198

109

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“…Of relevance are our recent demonstrations that repeated intraperitoneal injections of interleukin 6 (20 ug twice a day for 5 days) result in a sustained increase in agalactosyl IgG expression in DBA/1 mice (unpublished data). Interleukin 6 dysregulation is thought to contribute to the pathogenesis of rheumatoid arthritis (29) and elevated levels of interleukin 6 are present in mice with CIA (30).…”

Section: Methodsmentioning

confidence: 99%

Agalactosyl glycoforms of IgG autoantibodies are pathogenic.

Rademacher

Williams

Dwek

1994

Proc. Natl. Acad. Sci. U.S.A.

233

161

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IgG from the serum ofa rheumatoid arthritis patient has been shown to be arthritogenic in the murine passive transfer system (11). These latter observations are consistent with the hypothesis that localized synovial anti-type II collagen autoantibody production in human patients with rheumatoid arthritis may contribute to joint destruction.Despite the excellent correlation between disease activity and level of agalactosyl IgG in rheumatoid arthritis, it is still unclear whether this form of IgG is simply a marker for inflammation or is more directly involved in pathogenesis. In this paper, we attempt to resolve this issue by using the murine CIA model. MATERIALS AND METHODS

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“…IL-6 is known as a major inflammatory cytokine and plays an important rule for pathogenesis of RA 17) and in RA model animals. 18,19) It is reported that genetic deficiency in IL-6 completely suppressed the development of arthritis in SKG mice. 20,31) Sera were collected from SKG mice after 12 weeks at injection of BG and then IL-6 concentration in serum was measured by enzyme linked immunosorbent assay (ELISA).…”

Section: Fig 1 Severity Of Arthritis Induced By Injection Of Bg Dermentioning

confidence: 99%

Cell Wall .BETA.-Glucan Derived from Candida albicans Acts as a Trigger for Autoimmune Arthritis in SKG Mice

Hida

Miura

Adachi

et al. 2007

Biological & Pharmaceutical Bulletin

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Rheumatoid arthritis (RA) is one of the most common systemic autoimmune diseases. It is characterized by chronic joint inflammation, the formation of a rheumatoid pannus and eventually, tissue degradation and joint destruction.1) Although there are newer and effective therapeutic approaches, the etiology of RA is unknown.Animal models of RA are used to investigate the pathogenesis and to develop therapeutic drugs. For example, collagen-induced arthritis (CIA) is an animal model of RA. 2,3)CIA is induced by inoculation with type II collagen (CII) emulsified with Freund's complete adjuvant (FCA) consisting of mineral oil (Freund's incomplete adjuvant) and heat-killed Mycobacterium, followed by a booster injection.3) In the classical CIA model, FCA is essential for the induction of arthritis in mice. These results suggested that the activation of immune systems by Mycobacterium components is necessary for induction of autoimmune diseases. Recently, we reported that particles of b-glucan (BG) derived from Candida albicans acted as an adjuvant for CIA.4) We used a BG prepared from C. albicans by oxidation with sodium hypochlorite (NaClO), oxidative-Candida albicans (OX-CA).5) The results suggested that not only bacterial components in FCA but also BG derived from C. albicans acted as an adjuvant for the induction of CIA.SKG mice also spontaneously develop chronic autoimmune arthritis as a consequence of a mutation of the gene encoding an SH2 domain of ZAP-70, a key signal transduction molecule for T-cells.6) SKG mice develop arthritis at about 2 months of age under conventional conditions. The symptoms of SKG such as bilateral swelling of finger, wrist and ankle joints, and the production of various autoantibodies, resemble human RA; however, in a strictly controlled specific pathogen-free (SPF) environment, SKG mice failed to develop chronic arthritis. 7) These results suggested that infection from environmental agents, especially fungal infections, is a trigger for the induction of arthritis in SKG. In fact, SKG mice injected with BG such as laminarin (LAM) derived from seaweed Laminaria digitata and curdlan derived from the bacterium Alcaligenes faecalis, developed arthritis under SPF conditions, but not LPS or CpG derived from bacteria or viruses 7) ; therefore, a combination of genetic and environmental factors such as fungi may evoke autoimmune arthritis in SKG mice.Although LAM and curdlan were used to induce arthritis in SKG mice, they were not derived from fungi; furthermore, LAM is polydispersed with a degree of structural heterogeneity.8) It was reported that TNF-alpha production was induced from human monocytes with BG-oligomer prepared from LAM but not original LAM. 9) As the structure and biological activity of LAM remain unclear, it is not suitable to use LAM as a pure BG associated with fungal infection.C. albicans is the most frequently isolated opportunistic fungal pathogen and is reported to have a role in the pathogenesis of arthritis. 4,10,11) In the present study, we examined whether BGs derived...

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Enhanced production of interleukin‐6 in mice with type II collagen–induced arthritis

Cited by 69 publications

References 39 publications

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

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

Agalactosyl glycoforms of IgG autoantibodies are pathogenic.

Cell Wall .BETA.-Glucan Derived from Candida albicans Acts as a Trigger for Autoimmune Arthritis in SKG Mice

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