Constitutive and Induced IL-18 Receptor Expression by Various Peripheral Blood Cell Subsets as Determined by Anti-hIL-18R Monoclonal Antibody

Kunikata, Toshio; Torigoe, Kakuji; Ushio, Shimpei; Okura, Takanori; Ushio, Chie; Yamauchi, Hiroshi; Ikeda, Masao; Ikegami, Hiromasa; Kurimoto, Masashi

doi:10.1006/cimm.1998.1376

Cited by 80 publications

(48 citation statements)

References 12 publications

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“…BAL fluid T cells in sarcoid cases showed enhanced expression of IL-12␤ 2 R (22) and most BAL fluid T cells differentiated into Th1 (or T cytotoxic 1) cells (24). The expression of IL-18R was also up-regulated in Th1 cells (35). With coadministration of rIL-12 and rIL-18, sarcoid BAL fluid cells produced markedly greater IFN-␥ production than did normal BAL fluid cells.…”

Section: Discussionmentioning

confidence: 99%

IL-12 and IL-18 Are Increased and Stimulate IFN-γ Production in Sarcoid Lungs

Shigehara

Shijubo²,

Ohmichi

et al. 2001

The Journal of Immunology

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166

101

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Sarcoidosis is a systemic chronic granulomatous disease of unknown cause. Recent investigations revealed that the cytokine profile in inflamed lesions of sarcoidosis is Th1 dominant. To obtain better immunopathologic understanding of sarcoidosis, we examined the expression of IL-12 and IL-18 and their roles in IFN-γ production in pulmonary sarcoidosis. Sarcoid cases had significantly elevated levels of IL-12 (p40 and p70) and IL-18 in bronchoalveolar lavage (BAL) fluids compared with healthy subjects. IL-12 p70 and IL-18 were immunohistochemically expressed in the epithelioid cells and giant cells of sarcoid granulomas. Significant induction of IFN-γ, IL-12 p70, and IL-18 was observed from sarcoid BAL fluid cells with LPS stimulation, whereas LPS tended to induce only IL-12 p70 in BAL fluid cells from healthy subjects. Sarcoid cases had significantly greater IFN-γ induction with LPS stimulation than healthy subjects did. IL-18 mRNA expression was observed in freshly isolated sarcoid BAL fluid cells as well as in LPS-stimulated sarcoid BAL fluid cells, but IFN-γ and IL-12 mRNA expression was observed only in LPS-stimulated BAL fluid cells. Treatment with anti-IL-12- and anti-IL-18-neutralizing Abs significantly inhibited IFN-γ production from LPS-stimulated BAL fluid cells of sarcoid cases. Coadministration of rIL-12 or rIL-18 induced greater IFN-γ production in sarcoid BAL fluid cells than in normal BAL fluid cells. We concluded that bioactive IL-12 and IL-18 were produced in sarcoid BAL fluid cells and synergistically induced IFN-γ production, indicating important cytokines in the Th1 response of sarcoidosis.

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Section: Discussionmentioning

confidence: 99%

IL-12 and IL-18 Are Increased and Stimulate IFN-γ Production in Sarcoid Lungs

Shigehara

Shijubo²,

Ohmichi

et al. 2001

The Journal of Immunology

Self Cite

166

101

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“…IL-18 may mediate its effects directly by augmentation of IFN-γ production 6 10 23 24 or by enhancement of the expression of the IL-12R complex, thereby potentiating the effects of IL-12 25. While many studies have focused attention on the regulation of the IL-12R during Th cell differentiation, fewer have focused on regulation of the IL-18R 24 26 27 28 29. It has been widely assumed that the IL-18Rα is expressed only after T cell activation as the IL-18Rα could readily be detected on fully differentiated murine Th1 cells, but not on Th2 cells, either at the mRNA level or at the cell surface 22 23 24 26.…”

Section: Discussionmentioning

confidence: 99%

Regulation of Interleukin (Il)-18 Receptor α Chain Expression on Cd4+ T Cells during T Helper (Th)1/Th2 Differentiation

Smeltz

Chen

Hu‐Li

et al. 2001

The Journal of Experimental Medicine

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Interleukin (IL)-18 has been well characterized as a costimulatory factor for the induction of IL-12–mediated interferon (IFN)-γ production by T helper (Th)1 cells, but also can induce IL-4 production and thus facilitate the differentiation of Th2 cells. To determine the mechanisms by which IL-18 might regulate these diametrically distinct immune responses, we have analyzed the role of cytokines in the regulation of IL-18 receptor α chain (IL-18Rα) expression. The majority of peripheral CD4+ T cells constitutively expressed the IL-18Rα. Upon antigen stimulation in the presence of IL-12, marked enhancement of IL-18Rα expression was observed. IL-12–mediated upregulation of IL-18Rα required IFN-γ. Activated CD4+ T cells that expressed low levels of IL-18Rα could produce IFN-γ when stimulated with the combination of IL-12 and IL-18, while CD4+ cells which expressed high levels of IL-18Rα could respond to IL-18 alone. In contrast, T cell stimulation in the presence of IL-4 resulted in a downregulation of IL-18Rα expression. Both IL-4−/− and signal transducer and activator of transcription (Stat)6−/− T cells expressed higher levels of IL-18Rα after TCR stimulation. Furthermore, activated T cells from Stat6−/− mice produced more IFN-γ in response to IL-18 than wild-type controls. Thus, positive/negative regulation of the IL-18Rα by the major inductive cytokines (IL-12 and IL-4) determines the capacity of IL-18 to polarize an immune response.

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“…However, in another report, IL-12 failed to up-regulate IL-18R␣ expression during Th1 polarization of spleen naive T cells together with anti-CD3 unless IL-2 was present (25). Eventually, expression of IL-18R␣ on human PBMC, detected with a specific Ab, could be up-regulated by IL-12 only on NK cells, not on CD4 ϩ or CD8 ϩ cells, in the absence of costimulation (39). These data may be only apparently contrasting, as it should be taken into account that different cell populations in different stages of polarization/activation were considered.…”

Section: Discussionmentioning

confidence: 99%

Lymphocytes from Autoimmune MRLlpr/lprMice Are Hyperresponsive to IL-18 and Overexpress the IL-18 Receptor Accessory Chain

Neumann

Giudice

Ciaramella

et al. 2001

The Journal of Immunology

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MRL lpr/lpr mice spontaneously develop a severe autoimmune lupus syndrome characterized by strong autoantibody production and massive lymphoproliferation, in which IFN-γ plays a major pathogenic effect. The role of the IFN-γ-inducing cytokine IL-18 in the autoimmune syndrome of lpr/lpr mice has been investigated. In response to IL-18, lymph node cells of lpr/lpr mice produce significant amounts of IFN-γ and proliferate more potently as compared with cells from +/+ mice. Cells likely responsible for such hyperresponsiveness to IL-18 include NK cells and the CD4+/CD8+ self-reactive T lymphocytes characteristically present in lymph nodes of lpr/lpr mice. Analysis of the expression of IL-18R complex revealed that mRNA for the IL-18Rα-chain is constitutively expressed at similar level both in +/+ and lpr/lpr lymphocytes. In contrast, the expression of the accessory receptor chain IL-18Rβ is low in unstimulated +/+ cells but significantly high in lpr/lpr cells. Thus, the abnormally high expression of the IL-18R chain IL-18Rβ could be one of the causes of the hyperresponsiveness of lpr/lpr cells to IL-18 at the basis of consequent enhancement of IFN-γ production and development of IFN-γ-dependent autoimmune pathology.

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Constitutive and Induced IL-18 Receptor Expression by Various Peripheral Blood Cell Subsets as Determined by Anti-hIL-18R Monoclonal Antibody

Cited by 80 publications

References 12 publications

IL-12 and IL-18 Are Increased and Stimulate IFN-γ Production in Sarcoid Lungs

IL-12 and IL-18 Are Increased and Stimulate IFN-γ Production in Sarcoid Lungs

Regulation of Interleukin (Il)-18 Receptor α Chain Expression on Cd4+ T Cells during T Helper (Th)1/Th2 Differentiation

Lymphocytes from Autoimmune MRLlpr/lprMice Are Hyperresponsive to IL-18 and Overexpress the IL-18 Receptor Accessory Chain

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