The balance of Th1/Th2 cytokines in rheumatoid arthritis

Schulze‐Koops, Hendrik; Kalden, Joachim R.

doi:10.1053/berh.2001.0187

Cited by 241 publications

(168 citation statements)

References 48 publications

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“…However, the variable efficacy attained in human arthritis patients using existing IL-1 and TNFα inhibitors coupled with the demonstrated utility of targeting other pro-inflammatory entities [29,30] clearly suggests that other molecules may also drive disease. Many pro-inflammatory cytokines (IL-6, IL-12, IL-15, IL-18 [for review, see [26]] and IL-17 [25]) and chemokines (CCL2 [27] and CXCL8 [28]) as well as the proresorptive cytokine RANKL [45] have been implicated as potential arthritis mediators based on their presence within inflamed joints or because anticytokine biologics have been shown to reduce disease severity in animal arthritis models [26,55,56]. Accordingly, we devised the current experiment in a standard rat AIA model of immune-mediated joint disease to test two hypotheses.…”

Section: Discussionmentioning

confidence: 99%

The Evolving Systemic and Local Biomarker Milieu at Different Stages of Disease Progression in Rat Adjuvant-Induced Arthritis

et al. 2008

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Introduction Rats with adjuvant-induced arthritis (AIA) were necropsied on 14 occasions during preclinical, acute clinical and chronic clinical stages of AIA progression to characterize local (joint protein extracts) and systemic (serum) levels of mediators regulating inflammation and bone erosion in conjunction with lymphoid tissue-specific leukocyte kinetics. Results Systemic increases in alpha1 acid glycoprotein, tumor necrosis factor-α (TNFα), interleukin (IL)-17, transforming growth factor beta (TGFβ), and chemokine (C-C motif) ligand 2 (CCL2) together with local IL-1α/β and TGFβ enrichment and local lymphoid hyperplasia preceded the onset of clinical disease and joint damage. Systemic upregulation of TNFα, IL-6, IL-17, TGFβ, IL-18, CCL2, receptor activator of nuclear factor-κβ ligand (RANKL), and prostaglandin E 2 during acute and/or chronic AIA coincided with systemic leukocytosis and CD4+ T cell increase in blood and spleen. In contrast, progression of joint erosions during clinical AIA was associated with intraarticular increases in IL-1α/β, IL-6, RANKL, IL-17, TGFβ, CCL2, and KC/GRO and also a dramatic decline in osteoprotegerin. Conclusion These data indicate that systemic and local events in inflammatory arthritis are discrete processes, driven by multiple cellular and humoral mediators with distinct kinetic profiles.

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Section: Discussionmentioning

confidence: 99%

The Evolving Systemic and Local Biomarker Milieu at Different Stages of Disease Progression in Rat Adjuvant-Induced Arthritis

et al. 2008

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“…CIA is a frequently used mouse model of inflammatory rheumatoid arthritis that is both Ab and T cell dependent (35,36). It has been previously demonstrated that mouse strains prone to autoimmune diabetes have an increased number of T cells expressing CD40 that correlates with development of pathology (14).…”

Section: Cd40 Expression On T Cells From Mice With Ciamentioning

confidence: 99%

A Costimulatory Function for T Cell CD40

Munroe

Bishop

2007

The Journal of Immunology

100

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CD40 plays a significant role in the pathogenesis of inflammation and autoimmunity. B cell CD40 directly activates cells, which can result in autoantibody production. T cells can also express CD40, with an increased frequency and amount of expression seen in CD4+ T lymphocytes of autoimmune mice, including T cells from mice with collagen-induced arthritis. However, the mechanisms of T cell CD40 function have not been clearly defined. To test the hypothesis that CD40 can serve as a costimulatory molecule on T lymphocytes, CD40+ T cells from collagen-induced arthritis mice were examined in parallel with mouse and human T cell lines transfected with CD40. CD40 served as effectively as CD28 in costimulating TCR-mediated activation, including induction of kinase and transcription factor activities and production of cytokines. An additional enhancement was seen when both CD40 and CD28 signals were combined with AgR stimulation. These findings reveal potent biologic functions for T cell CD40 and suggest an additional means for amplification of autoimmune responses.

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“…This balance can be disrupted by local inflammation to cause dysregulated bone remodeling that often leads to bone erosion in inflammatory bone diseases such as arthritis and chronic osteomyelitis (1)(2)(3). Bone formation and resorption are mediated by osteoblasts and osteoclasts, respectively.…”

mentioning

confidence: 99%

“…For example, activated T cells not only express RANKL themselves (13), but also secrete IL-17 to upregulate RANKL expression on osteoblasts (6) to induce osteoclastogenesis. Much work has also been devoted to the roles of CD4 effector subsets, the type 1 and type 2 Th (Th1 and Th2) cells in inflammatory arthritis (2). Th1 and Th2 cells are characterized by their mutually exclusive cytokine profiles, with Th1 cells producing IFN-␥, whereas Th2 cells produce IL-4, -5, and -13 (15).…”

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confidence: 99%

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Differential Regulation of Osteoblast Activity by Th Cell Subsets Mediated by Parathyroid Hormone and IFN-γ

Young

Mikhalkevich

Yan

et al. 2005

The Journal of Immunology

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Bone loss is a typical pathological feature of chronic inflammatory bone diseases including rheumatoid arthritis, in which CD4 effector T cells play critical roles. We found that activated mouse Th2 and not Th1 cells produced the parathyroid hormone (PTH). Unlike in the parathyroid cells, PTH expression in Th2 cells was not regulated by the fluctuation of calcium level, but rather it required the full activation of the T cells. Although PTH was expressed in immature Th2 cells, and its receptor was transiently expressed during Th1 and Th2 cell differentiation, PTH did not significantly affect the outcome of the differentiation. In primary osteoblasts cultured in Th2 cell condition medium, the alkaline phosphatase (ALP) activity was maintained at a basal level. However, antagonizing PTH in the condition medium resulted in a significant reduction of the ALP activity. These results demonstrated an important role of the Th2 cell-derived PTH in maintaining the bone-forming activity of the osteoblasts under inflammatory conditions. In osteoblasts cultured in the Th1 cell condition medium, the ALP activity was significantly suppressed. Neutralizing IFN-␥ alleviated the suppression. Conversely, treatment of osteoblasts with IFN-␥ suppressed the ALP activity. Unlike ALP, expression of the major bone matrix proteins by the osteoblasts was only minimally affected by either Th1 or Th2 cytokine environment. In addition, the Th2 cytokine environment also regulated to expression of receptor activator of NF-B ligand and osteoprotegerin through both PTH-dependent and -independent mechanisms. Our study therefore identified new regulatory events in bone remodeling under inflammatory conditions.

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The balance of Th1/Th2 cytokines in rheumatoid arthritis

Cited by 241 publications

References 48 publications

The Evolving Systemic and Local Biomarker Milieu at Different Stages of Disease Progression in Rat Adjuvant-Induced Arthritis

The Evolving Systemic and Local Biomarker Milieu at Different Stages of Disease Progression in Rat Adjuvant-Induced Arthritis

A Costimulatory Function for T Cell CD40

Differential Regulation of Osteoblast Activity by Th Cell Subsets Mediated by Parathyroid Hormone and IFN-γ

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