Rheumatoid arthritis exacerbation caused by exogenous interleukin-12

Peeva, Elena; Fishman, Ari D.; Goddard, Gisele Zandman; Wadler, Scott; Barland, Peter

doi:10.1002/1529-0131(200002)43:2<461::aid-anr29>3.0.co;2-7

Cited by 29 publications

(10 citation statements)

References 7 publications

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“…These findings suggest that blocking IL-12 with mAbs may be a useful therapeutic strategy for RA. Consistent with our suggestion, it was reported that RA is exacerbated by multiple injections of IL-12 for therapeutic purposes in metastatic cervical cancer (27). Alternatively, strategies to block the functional activity of IL-12R-expressing effector cells, such as NKT cells may also be helpful in treating RA.…”

Section: Discussionsupporting

confidence: 89%

IL-12p35 Promotes Antibody-Induced Joint Inflammation by Activating NKT Cells and Suppressing TGF-β

Park

Kim

Ahn

et al. 2010

The Journal of Immunology

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The functional role of IL-12 in rheumatoid arthritis is controversial. Moreover, whether IL-12 contributes to regulation of Ab-induced joint inflammation remains unclear. To address these issues, we explored the functional roles of IL-12 in Ab-induced arthritis using the K/BxN serum transfer model. IL-12p35−/− and IL-12Rβ2−/− mice were resistant to the development of arthritis. Injection of K/BxN serum into IL-12p40–yellow fluorescence protein reporter (yet40) mice induced CD11b+ cells, CD11c+ cells, and Gr-1+ granulocytes to produce IL-12p40 in the joints. The levels of IFN-γ, IL-4, and IL-6 production were lower in joint tissues of IL-12p35−/− and IL-12Rβ2−/− mice than in B6 mice, whereas levels of TGF-β expression were higher. Administering IL-12p35−/− mice rIL-12 or IFN-γ restored joint inflammation and suppressed TGF-β production in joint tissues. Moreover, administering neutralizing anti–TGF-β mAb enhanced joint inflammation. Among the immune cells that infiltrated joint tissues during Ab-induced arthritis, NKT cells expressed IL-12β2 receptors. Furthermore, the adoptive transfer of splenocytes from B6 or Gr-1+ granulocyte-depleted mice restored joint inflammation in IL-12Rβ2−/− mice as much as in B6 mice, whereas splenocytes from Jα18−/− mice did not. These findings indicate that signals via IL-12β2 receptors on NKT cells play a critical role in the development of Ab-induced arthritis. The IL-12p35/IFN-γ axis promotes Ab-induced joint inflammation by activating NKT cells and suppressing TGF-β, which may provide novel information for the development of new therapeutic strategies for the inhibition of rheumatoid arthritis.

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Section: Discussionsupporting

confidence: 89%

IL-12p35 Promotes Antibody-Induced Joint Inflammation by Activating NKT Cells and Suppressing TGF-β

Park

Kim

Ahn

et al. 2010

The Journal of Immunology

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“…[48][49][50][51] Reciprocally, administration of recombinant IFN-␥ to treat malignant or infectious diseases can result in manifestation or exacerbation of autoimmune symptoms, 52 an effect that was also attributed to the IFN-␥-inducing factor IL-12. 53 Consequences of IFN-␥ release in the inflamed tissue include induction of other proinflammatory mediators, such as IL-6, IL-8, and IL-15, as was demonstrated in coculture experiments of synovial T cells with synovial fibroblasts from active RA patients. 54 Although several rodent arthritis models substantiate the view that IFN-␥ contributes to joint inflammation, [55][56][57][58] IFN-␥-secreting Th cells may also serve regulatory functions by restriction of the primary expansion of Th1 cells and suppression of Th17 cell development.…”

Section: Discussionmentioning

confidence: 94%

Cytokine-induced human IFN-γ–secreting effector-memory Th cells in chronic autoimmune inflammation

Sattler

Wagner

Rossol

et al. 2009

Blood

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IntroductionProduction of interferon-␥ (IFN-␥) by T-helper1 (Th1) cells is a key feature of both protective and pathologic immune responses. Control and clearance of bacterial and viral infections strictly depend on antigen-specific IFN-␥-secreting Th cells. 1,2 It is also undisputed that Th1 cells of the effector-memory phenotype predominate in inflamed tissues in human autoimmune diseases, such as rheumatoid arthritis (RA), [3][4][5] where they compose up to 80% of the T-cell infiltrate. 6 Nonetheless, how such cells get activated at sites of chronic inflammation remains an unsolved issue. Recent reports have challenged the concept that IFN-␥ release by T cells strictly depends on T-cell receptor (TCR) ligation: in in vitro-generated murine Th1-effector cells, IFN-␥ production is inducible in a TCR-independent manner by the cytokines interleukin-12 (IL-12) and IL-18. 7 IL-12R-downstream STAT4 and IL-18R-dependent GADD45-␤, which activates p38 mitogen-activated protein kinase (MAPK), were identified as essential signaling components. 8,9 Although infection models suggest that such a mechanism evolved to provide an early source of IFN-␥ contributing to host protection, 10,11 it was at the same time postulated to promote inflammatory circuits in autoimmunity. 12 In contrast to murine Th1 cells, however, stimulation of human resting Th cells with IL-12 and IL-18 induces only minute amounts of IFN-␥ 13 but boosts cytokine production in synergy with TCR ligation. 14 Th cells isolated from synovial infiltrates of RA patients exhibit a differentiated effector-memory Th1 phenotype, reflected, for example, by expression of IL-12R and IL-18R. 15 Because elevated levels of several proinflammatory mediators, including IL-12 and IL-18, were found to correlate with disease severity, 16,17 we wondered whether cytokine-induced IFN-␥ production in human Th cells in the absence of antigenic stimulation is functional at all in vitro and of relevance in vivo in human autoimmunity.We demonstrate here that a subset of human resting effectormemory Th cells, characterized by ex vivo expression of IL-18R␣, IL-12R, and CCR5, can be induced to secrete IFN-␥ by cytokines present at sites of chronic inflammation. IL-2R ␥-chain (␥ c ) signaling via JAK3, in addition to IL-12R and IL-18R ligation, is essential for TCR-independent induction of IFN-␥ production. Cytokine-induced IFN-␥ ϩ Th cells are sensitive to suppression by CD25 ϩϩ T regulatory cells and specifically lack 4-1BB (CD137) expression. Applying this activation marker, we provide evidence that almost all Th cells spontaneously secreting IFN-␥ ex vivo in synovial infiltrates from RA patients are cytokine-induced, for they characteristically lack 4-1BB expression. Our results support the notion that IFN-␥ production by Th cells in chronic autoimmune inflammation may be provoked solely by the cytokine environment, independent of triggering autoantigens. Methods Cell isolationPeripheral blood mononuclear cells (PBMCs) were isolated from peripheral blood of healthy donors by Ficoll-Hy...

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“…The role of IL‐12 in the induction of chronic Th1‐mediated diseases, such as experimental colitis and arthritis, is well known. IL‐12 exposure or the use of IL‐12‐deficient mice has revealed that IL‐12 is a crucial immune‐stimulatory cytokine for the development of experimentally induced arthritis (13, 15, 16). This is the first study showing that local overexpression of IL‐12 in combination with an acute inflammation generates a chronic immune‐mediated destructive process.…”

Section: Discussionmentioning

confidence: 99%

Local interleukin‐12 gene transfer promotes conversion of an acute arthritis to a chronic destructive arthritis

Joosten¹,

Heuvelmans‐Jacobs²,

Lubberts³

et al. 2002

Arthritis & Rheumatism

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Objective. To determine whether local overexpression of interleukin-12 (IL-12), a pleiotropic cytokine that promotes the development of naive T cells into Th1 cells, could aggravate murine streptococcal cell wall (SCW)-induced arthritis, a model of acute arthritis.Methods. C57BL/6 mice were injected intraarticularly with saline or with 10 7 plaque-forming units of control vector (Ad5del70-3) or IL-12 vector (AdmIL-12.1) into the right knee joint 1 day before intraarticular injection of 25 g of SCW fragments. The development of joint swelling, changes in chondrocyte proteoglycan (PG) synthesis, and joint destruction were examined thereafter.Results. In normal joints, high levels of IL-12 (20 ng/ml on day 1) could be detected after application of the AdmIL-12.1 vector. After 14 days, expression of IL-12 was still found locally, but IL-12 alone did not induce protracted inflammation. Local expression of IL-12, in combination with SCW, markedly aggravated SCW-induced arthritis, as determined by enhanced joint swelling and prolonged inhibition of chondrocyte PG synthesis. Histologic examination on day 21 showed a chronic inflammatory process, with persistent cartilage PG depletion, cartilage erosion, and VDIPEN neoepitope expression (indicative of metalloproteinase activation). The mixture of IL-12 with SCW fragments did not lead to a chronic destructive process in mice deficient for recombination-activating gene 2, indicating the involvement of lymphocytes. In addition, systemic flare of smoldering SCW arthritis, produced by intravenous injection of SCW fragments, was only seen in the AdmIL-12/SCW group.Conclusion. These results indicate that local overexpression of IL-12 promotes conversion of an acute arthritis to a chronic destructive immune-mediated process, which is more susceptible to flares.

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Rheumatoid arthritis exacerbation caused by exogenous interleukin-12

Cited by 29 publications

References 7 publications

IL-12p35 Promotes Antibody-Induced Joint Inflammation by Activating NKT Cells and Suppressing TGF-β

IL-12p35 Promotes Antibody-Induced Joint Inflammation by Activating NKT Cells and Suppressing TGF-β

Cytokine-induced human IFN-γ–secreting effector-memory Th cells in chronic autoimmune inflammation

Local interleukin‐12 gene transfer promotes conversion of an acute arthritis to a chronic destructive arthritis

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