Definition of a specific interaction between the early T lymphocyte activation 1 (Eta-1) protein and murine macrophages in vitro and its effect upon macrophages in vivo.

Singh, Rajesh; Patarca, Roberto; Schwartz, Joel L.; Singh, Pratima; Cantor, Harvey

doi:10.1084/jem.171.6.1931

Cited by 218 publications

(123 citation statements)

References 26 publications

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“…Based upon the studies in autoimmune animal models and those in rheumatoid arthritis in humans, OPN could be an important cytokine to be targeted as it is highly related to autoimmunity [10,13,30,50,[53][54][55]. The other important role of OPN is related to migration of inflammatory cells into the CNS [56]. There is evidence supporting the notion that OPN is critical to cell migration, including that of tumor cells [57].…”

Section: Discussionmentioning

confidence: 99%

Regulatory effects of IFN‐β on production of osteopontin and IL‐17 by CD4⁺ T Cells in MS

Chen

Nie

et al. 2009

Eur J Immunol

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IFN-b currently serves as one of the major treatments for MS. Its anti-inflammatory mechanism has been reported as involving a shift in cytokine balance from Th1 to Th2 in the T-cell response against elements of the myelin sheath. In addition to the Th1 and Th2 groups, two other important pro-inflammatory cytokines, IL-17 and osteopontin (OPN), are believed to play important roles in CNS inflammation in the pathogenesis of MS. In this study, we examined the potential effects of IFN-b on the regulation of OPN and IL-17 in MS patients. We found that IFN-b used in vitro at 0.5-3 ng/mL significantly inhibited the production of OPN in primary T cells derived from PBMC. The inhibition of OPN was determined to occur at the CD4 1 T-cell level. In addition, IFN-b inhibited the production of IL-17 and IL-21 in CD4 1 T cells. It has been described that IFN-b suppresses IL-17 production through the inhibition of a monocytic cytokine, the intracellular translational isoform of OPN. Our further investigation demonstrated that IFN-b also acted directly on the CD4 1 T cells to regulate OPN and IL-17 expression through the type I IFN receptor-mediated activation of STAT1 and suppression of STAT3 activity. Administration of IFN-b to EAE mice ameliorated the disease severity. Furthermore, spinal cord infiltration of OPN 1 and IL-17 1 cells decreased in IFN-b-treated EAE mice along with decreases in serum levels of OPN and IL-21. Importantly, decreased OPN production by IFN-b treatment contributes to the reduced migratory activity of T cells. Taken together, the results from both in vitro and in vivo experiments indicate that IFN-b treatment can down-regulate the OPN and IL-17 production in MS. This study provides new insights into the mechanism of action of IFN-b in the treatment of MS. IntroductionMS is a disease of the CNS characterized by chronic inflammatory and demyelinating processes [1]. CNS inflammation is considered as an important feature in MS pathology, and is directly associated with the disease process in MS [2]. Agents that have anti-inflammatory properties have been shown to suppress the disease activity to various degrees. MS is now commonly treated with an immunomodulatory agent, IFN-b, which has shown significant treatment efficacy and is Ã These authors contributed equally to the work. Eur. J. Immunol. 2009. 39: 2525-2536 Immunomodulation 2525 thought to involve a number of different mechanisms of action [3,4]. However, despite extensive clinical experience in the use of IFN-b, its mechanism of action has not been fully elucidated. Studies into its mechanism of action have revealed that anti-inflammatory properties of IFN-b function through the regulation of Th1 and Th2 cytokines [5,6]. Further, there is an evidence indicating that IFN-b promotes the production of IL-10 and inhibits the action of pro-inflammatory cytokines [7,8].Osteopontin (OPN), also known as early T lymphocyte activation-1, has been recently recognized as a pro-inflammatory cytokine promoting the production of IFN-g and IL-12 in macrophages...

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Section: Discussionmentioning

confidence: 99%

Regulatory effects of IFN‐β on production of osteopontin and IL‐17 by CD4⁺ T Cells in MS

Chen

Nie

et al. 2009

Eur J Immunol

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“…These findings demonstrate that OPN plays a role in not only afferent phase of EAU development, but also the efferent phase in which primed T cells respond to the immunogen, hIRBP peptide. Furthermore, it has been reported that OPN initiates migration of macrophages and dendritic cells to site of inflammation (10,43,44). Thus, M5 Ab may also diminish the migration of macrophages and dendritic cells to the inflammatory site.…”

Section: Discussionmentioning

confidence: 99%

Osteopontin Aggravates Experimental Autoimmune Uveoretinitis in Mice

Kitamura

Iwabuchi

Kawa

et al. 2007

The Journal of Immunology

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Human endogenous uveitis is a common sight-threatening intraocular inflammatory disease and has been studied extensively using a murine model of experimental autoimmune uveoretinitis (EAU). It is possibly mediated by Th1 immune responses. In the present study, we investigated the role of osteopontin (OPN), a protein with pleiotropic functions that contributes to the development of Th1 cell-mediated immunity. Accompanying EAU progression, OPN was elevated in wild-type (WT) mice that had been immunized with human interphotoreceptor retinoid-binding protein (hIRBP) peptide 1–20. OPN-deficient (OPN−/−) mice showed milder EAU progression in clinical and histopathological scores compared with those of WT mice. The T cells from hIRBP-immunized OPN−/− mice exhibited reduced Ag-specific proliferation and proinflammatory cytokine (TNF-α and IFN-γ) production compared with those of WT T cells. When hIRBP-immunized WT mice were administered M5 Ab reacting to SLAYGLR sequence, a cryptic binding site to integrins within OPN, EAU development was significantly ameliorated. T cells from hIRBP-immunized WT mice showed significantly reduced proliferative responses and proinflammatory cytokine production upon stimulation with hIRBP peptide in the presence of M5 Ab in the culture. Our present results demonstrate that OPN may represent a novel therapeutic target to control uveoretinitis.

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“…A macrophage-activating cytokine termed Eta-1 depends on an RGD sequence for its interaction with macrophages (Singh et al, 1990). This is reminiscent of the dependence of several matrix proteins on RGD sequences for their binding to integrins (Ruoslahti and Pierschbacher, 1986).…”

Section: Some Adhesion Receptors Can Act Like Cytokine Receptorsmentioning

confidence: 99%

Cytokines in context.

Nathan

Sporn

1991

The Journal of Cell Biology

770

283

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Definition of a specific interaction between the early T lymphocyte activation 1 (Eta-1) protein and murine macrophages in vitro and its effect upon macrophages in vivo.

Cited by 218 publications

References 26 publications

Regulatory effects of IFN‐β on production of osteopontin and IL‐17 by CD4⁺ T Cells in MS

Regulatory effects of IFN‐β on production of osteopontin and IL‐17 by CD4⁺ T Cells in MS

Osteopontin Aggravates Experimental Autoimmune Uveoretinitis in Mice

Cytokines in context.

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Definition of a specific interaction between the early T lymphocyte activation 1 (Eta-1) protein and murine macrophages in vitro and its effect upon macrophages in vivo.

Cited by 218 publications

References 26 publications

Regulatory effects of IFN‐β on production of osteopontin and IL‐17 by CD4+ T Cells in MS

Regulatory effects of IFN‐β on production of osteopontin and IL‐17 by CD4+ T Cells in MS

Osteopontin Aggravates Experimental Autoimmune Uveoretinitis in Mice

Cytokines in context.

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Product

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Regulatory effects of IFN‐β on production of osteopontin and IL‐17 by CD4⁺ T Cells in MS

Regulatory effects of IFN‐β on production of osteopontin and IL‐17 by CD4⁺ T Cells in MS