Expression of Cell Adhesion Molecules and Cytokines in Murine Antigen-Induced Arthritis

Hersmann, G.; Kriegsmann, Jörg; Simon, J.; Hüttich, C.; Bräuer, Rolf

doi:10.3109/15419069809069761

Cited by 26 publications

(25 citation statements)

References 56 publications

(31 reference statements)

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“…This response can be blocked with anti-LFA-1 Ab demonstrating that SEB-induced IL-2 production is LFA-1 dependent. 50 values generated from the inhibition of IL-2 mRNA are similar to those obtained in the MLR assay (see Table I). …”

Section: Resultssupporting

confidence: 63%

“…For example, T cells removed from the synovial fluid of RA patients express LFA-1 in a high avidity state on their cell surface, prompting the authors to suggest that synovial environment promotes and/or maintains T cells in an activated state (49). Likewise, LFA-1 and ICAM-1 expression is significantly increased in the pannus, the synovial lining layer, and the synovial infiltrate in murine Ag-induced arthritis (50). In this model, the expression of inflammatory cytokines paralleled that of LFA-1 and ICAM-1.…”

Section: Discussionmentioning

confidence: 55%

“…Thus, if compounds exhibited relatively high protein binding, one would expect that the IC 50 values obtained in the MLR assays would be higher than those generated from the adhesion assays conducted in the absence of serum. Because BMS-587101 was 95% protein bound in human serum, it was not surprising that the IC 50 value for inhibition in the MLR was higher than that observed in the adhesion assay, with an IC 50 of 280 6 20 nM (Table I). …”

Section: Resultsmentioning

confidence: 99%

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An LFA-1 (αLβ2) Small-Molecule Antagonist Reduces Inflammation and Joint Destruction in Murine Models of Arthritis

Suchard

Stetsko

Davis

et al. 2010

The Journal of Immunology

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LFA-1 appears to play a central role in normal immune responses to foreign Ags. In autoimmune or inflammatory diseases, there is increased expression of LFA-1 and/or its counterligand, ICAM-1. Others have demonstrated that the targeted disruption of LFA-1:ICAM interactions, either by gene deletion or Ab treatment in mice, results in reduced leukocyte trafficking, inflammatory responses, and inhibition of inflammatory arthritis in the K/BxN serum transfer model. However, there has been little success in finding a small-molecule LFA-1 antagonist that can similarly impact rodent models of arthritis. In this paper, we present the first reported example of an LFA-1 small-molecule antagonist, BMS-587101, that is efficacious in preclinical disease models. In vitro, BMS-587101 inhibited LFA-1–mediated adhesion of T cells to endothelial cells, T cell proliferation, and Th1 cytokine production. Because BMS-587101 exhibits in vitro potency, cross-reactivity, and oral bioavailability in rodents, we evaluated the impact of oral administration of this compound in two different models of arthritis: Ab-induced arthritis and collagen-induced arthritis. Significant impact of BMS-587101 on clinical score in both models was observed, with inhibition comparable or better than anti-mouse LFA-1 Ab. In addition, BMS-587101 significantly reduced cytokine mRNA levels in the joints of Ab-induced arthritis animals as compared with those receiving vehicle alone. In paws taken from the collagen-induced arthritis study, the bones of vehicle-treated mice had extensive inflammation and bone destruction, whereas treatment with BMS-587101 resulted in marked protection. These findings support the potential use of an LFA-1 small-molecule antagonist in rheumatoid arthritis, with the capacity for disease modification.

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Section: Resultssupporting

confidence: 63%

Section: Discussionmentioning

confidence: 55%

Section: Resultsmentioning

confidence: 99%

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An LFA-1 (αLβ2) Small-Molecule Antagonist Reduces Inflammation and Joint Destruction in Murine Models of Arthritis

Suchard

Stetsko

Davis

et al. 2010

The Journal of Immunology

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“…28 and 29). In murine AIA, temporal changes in TNF␣, IL-1␤, and IFN␥ expression occur during the acute phase, 1 day after arthritis induction (30,31). We observed that levels of TNF␣ and IL-1␤ expression in synovial tissues were not significantly different between IFN␥ Ϫ/Ϫ and IFN␥ ϩ/ϩ mice at this time; furthermore, titers of antibody to mBSA were comparable (data not shown).…”

Section: Discussionsupporting

confidence: 48%

Interferon‐γ protects against the development of structural damage in experimental arthritis by regulating polymorphonuclear neutrophil influx into diseased joints

Williams

Richards

Thomas

et al. 2007

Arthritis & Rheumatism

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Objective. Local interaction between soluble mediators within the inflamed synovium is a key factor that governs the pathologic outcome of inflammatory arthritides. Our aim was to investigate the interplay between the Th1 lymphokine interferon-␥ (IFN␥) and pivotal cytokines that drive rheumatoid arthritis ( ) mice. Joint swelling was measured and histologic analysis was performed in order to assess changes in both inflammatory and degenerative parameters in vivo. In vitro, the influence of IFN␥ in regulating IL-1␤-and TNF␣-driven CXCL8 and CCL2 production was quantified by enzyme-linked immunosorbent assay.Results. In murine AIA, both inflammatory and degenerative arthritis parameters were significantly exacerbated in the absence of IFN␥. IFN␥ appeared to be a crucial factor in regulating CXCR2؉ neutrophil influx in the joint. In in vitro studies using RA fibroblastlike synoviocytes, IFN␥ modulated both IL-1␤-and TNF␣-driven chemokine synthesis, resulting in the down-regulation of CXCL8 production.Conclusion. IFN␥ exerts antiinflammatory, chondroprotective, and antiosteoclastogenic effects in murine AIA through a mechanism that involves the regulation of chemokine synthesis and local neutrophil recruitment. These studies suggest a potential therapeutic role of modulating IFN␥ signaling in the treatment of inflammatory arthritides.

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“…As previously described (23), serial cryosections of 5-m thickness from knee joints of IFN-␥ Ϫ/Ϫ mice at the stage of maximum cellular infiltration 1 day after AIA induction were fixed in acetone, blocked with 4% milk/ Tris, and stained with primary 10 g/ml rat mAbs directed against mouse Mac-1 (macrophages and neutrophil granulocytes; Medac), F4/80 (macrophages; Serotec), Gr-1 (neutrophil granulocytes), CD4 (Th cells), or B220 (B cells; all from BD Biosciences) for 1 h at 22°C, followed by incubation with biotinylated secondary goat anti-rat IgG Abs (DakoCytomation) and fixation in 1% formalin. Tris buffer was used for subsequent washing steps.…”

Section: Immunohistochemical Examinationsmentioning

confidence: 99%

Exacerbation of Antigen-Induced Arthritis in IFN-γ-Deficient Mice As a Result of Unrestricted IL-17 Response

Irmler

Gajda

Bräuer

2007

The Journal of Immunology

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121

103

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Proinflammatory Th1 responses are believed to be involved in the induction and perpetuation of rheumatoid arthritis. However, the role of IFN-γ, the major cytokine produced by Th1 cells, is still incompletely defined. In the present study, we investigated the effects of IFN-γ deficiency (IFN-γ−/−) on the course of experimental murine Ag-induced arthritis (AIA). In the acute stage of disease, IFN-γ−/− AIA mice showed significantly increased inflammatory responses compared with wild-type C57BL/6 AIA mice, i.e., exacerbated joint swelling, increased delayed-type hypersensitivity reaction, and increased histopathological scores of arthritis. Intraarticular administration of exogenous IFN-γ at induction of AIA significantly suppressed these acute aggravation effects. Stimulated cells isolated from lymph nodes and spleen of IFN-γ−/− AIA mice showed increased production of IL-2, IL-4, IL-5, IL-6, but most prominently of IL-17. These elevations were paralleled by decreased humoral immune responses, with low serum levels of total and Ag-specific IgG (IgG1, IgG2ab, IgG2b, IgG3). At immunohistology, the knee joints of IFN-γ−/− AIA mice showed massive neutrophil granulocyte infiltration. Treatment with mAbs neutralizing IL-17 diminished the acute inflammation. In vitro, Th cell expansion and production of IL-17 upon restimulation were effectively and dose dependently inhibited by IFN-γ. These results clearly demonstrate that IFN-γ has anti-inflammatory properties during the initial phase of AIA, and indicate that IFN-γ deficiency exerts disease-promoting effects, preferentially via IL-17-modulated pathways.

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Expression of Cell Adhesion Molecules and Cytokines in Murine Antigen-Induced Arthritis

Cited by 26 publications

References 56 publications

An LFA-1 (αLβ2) Small-Molecule Antagonist Reduces Inflammation and Joint Destruction in Murine Models of Arthritis

An LFA-1 (αLβ2) Small-Molecule Antagonist Reduces Inflammation and Joint Destruction in Murine Models of Arthritis

Interferon‐γ protects against the development of structural damage in experimental arthritis by regulating polymorphonuclear neutrophil influx into diseased joints

Exacerbation of Antigen-Induced Arthritis in IFN-γ-Deficient Mice As a Result of Unrestricted IL-17 Response

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