Immunomodulation by an Adenylate Cyclase Activator, NKH477,in Vivoandin Vitro

Furukawa, Yutaka; Matsumori, Akira; Hirozane, Toshiro; Matsui, Shigeo; Sato, Yukiyasu; Ono, Koh; Sasayama, Shígetake

doi:10.1006/clin.1996.0047

Cited by 13 publications

(11 citation statements)

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“…On the other hand, in transplantation, PGE 2 -induced elevation of cAMP exerts a beneficial effect on allograft survival by modulating T cell function (48). Enhanced PGE 2 production reduces Th1 cytokine levels, independently of those of Th2 cytokines, in the local graft environment after donor-specific blood transfusion, which induces donor-specific intragraft suppressor factors, accompanied by reduced local and systemic immune activation (49).…”

Section: Discussionmentioning

confidence: 99%

Prostaglandin E2 Inhibits IL-18-Induced ICAM-1 and B7.2 Expression Through EP2/EP4 Receptors in Human Peripheral Blood Mononuclear Cells

Takahashi¹,

Ishibashi²,

Yoshino

et al. 2002

The Journal of Immunology

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Costimulatory molecules play important roles in immune responses. In the present study we investigated the effects of PGE2 on the expression of ICAM-1, B7.1, and B7.2 on monocytes in IL-18-stimulated PBMC using FACS analysis. Addition of PGE2 to PBMC inhibited ICAM-1 and B7.2 expression elicited by IL-18 in a concentration-dependent manner. We examined the involvement of four subtypes of PGE2 receptors, EP1, EP2, EP3, and EP4, in the modulatory effect of PGE2 on ICAM-1 and B7.2 expression elicited by IL-18, using subtype-specific agonists. ONO-AE1–259-01 (EP2R agonist) inhibited IL-18-elicited ICAM-1 and B7.2 expression in a concentration-dependent manner with a potency slightly less than that of PGE2, while ONO-AE1-329 (EP4R agonist) was much less potent than PGE2. The EP2/EP4R agonist 11-deoxy-PGE1 mimicked the effect of PGE2 with the same potency. ONO-D1-004 (EP1R agonist) and ONO-AE-248 (EP3R agonist) showed no effect on IL-18-elicited ICAM-1 or B7.2 expression. These results indicated that EP2 and EP4Rs were involved in the action of PGE2. Dibutyryl cAMP and forskolin down-regulated ICAM-1 and B7.2 expression in IL-18-stimulated monocytes. As EP2 and EP4Rs are coupled to adenylate cyclase, we suggest that PGE2 down-regulates IL-18-induced ICAM-1 and B7.2 expression in monocytes via EP2 and EP4Rs by cAMP-dependent signaling pathways. The fact that anti-B7.2 as well as anti-ICAM-1 Ab inhibited IL-18-induced cytokine production implies that PGE2 may modulate the immune response through regulation of the expression of particular adhesion molecules on monocytes via EP2 and EP4Rs.

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Section: Discussionmentioning

confidence: 99%

Prostaglandin E2 Inhibits IL-18-Induced ICAM-1 and B7.2 Expression Through EP2/EP4 Receptors in Human Peripheral Blood Mononuclear Cells

Takahashi¹,

Ishibashi²,

Yoshino

et al. 2002

The Journal of Immunology

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“…It has been shown that elevation of intracellular cAMP inhibits inflammation-associated gene expression in vitro (Pahan et al, 1997;Mustafa and Olson, 1998), as well as promotes cell survival and cardiac function and contractility (Hanna et al, 1993;Furukawa et al, 1996); however, the func- Figure 1. Treatment with db-cAMP inhibits the expression of pro-inflammatory cytokines in transplanted hearts of allograft recipient rats.…”

Section: Introductionmentioning

confidence: 99%

Cyclic AMP prolongs graft survival by suppressing apoptosis and inflammatory gene expression in acute cardiac allograft rejection

et al. 2010

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This study was designed to investigate the effects of cAMP on immune regulation and apoptosis during acute rat cardiac allograft rejection. We found that the production of immune markers such as inflammatory cytokines (IL-1β, IL-6, and TNF-α), iNOS expression, and nitric oxide (NO) production, was significantly increased in the blood and transplanted hearts of allograft recipients, but not of isograft controls. These increases were effectively suppressed by the administration of the membrane permeable cAMP analog dibutyryl cAMP (db-cAMP). Administration of db-cAMP reduced allograft-induced elevation of several biochemical markers, such as adhesion molecule expression, iron-nitrosyl complex formation, caspase-3 activation, and apoptotic DNA fragmentation in an animal model. Furthermore, treatment of allograft recipients with db-cAMP prolonged median graft survival to 11 days compared with a median graft survival time of 8 days in saline-treated allograft recipients. These results suggest that db-cAMP exerts a beneficial effect on murine cardiac allograft survival by modulating allogeneic immune response and cytotoxicity.

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“…19 Nevertheless, we have shown that NKH477 significantly prolonged lung allograft survival time in a dosedependent manner, as reported previously for the cardiac allografts. 10 Histopathological findings indicated that cellular infiltration and graft destruction were significantly less prominent in the lung allografts treated with the NKH477 than those in the untreated group. Thus, reduced histological rejection appeared to contribute to prolonged allograft survival in NKH477-treated animals.…”

Section: Discussionmentioning

confidence: 89%

“…A previous study by Furukawa et al demonstrated in vitro inhibition of IL-2 by NKH477. 10 In addition, cAMPelevating agents have been shown to inhibit IFN-␥-producing Th1 development by selective inhibition of IL-12. 30 The evaluation of intragraft deposition of immunoglobulin (Ig) by ELISA also showed that the deposition of IgG, not IgM, of which synthesis and isotype switching are regulated by IL-2 and IFN-␥, was significantly less in the allografts of NKH477-treated recipients (data not shown).…”

Section: Discussionmentioning

confidence: 99%

“…6 Subsequently, prolonged survival of murine cardiac allografts was demonstrated. 10 Although immunomodulation by NKH477 was shown in vitro, the in vivo mechanism of its efficacy was not addressed previously in the report. Furthermore, because the inotropic effects of NKH477 directly acting on cardiomyocytes might contribute to the improvement of allograft survival, the animal model that uses cardiac allografts itself is not ideal to investigate the immunosuppressive activity of NKH477.…”

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confidence: 92%

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Antiproliferative effects of NKH477, a forskolin derivative, on cytokine profile in rat lung allografts

Nakashima¹,

Morikawa²,

Komatsu³

et al. 2005

The Journal of Heart and Lung Transplantation

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Immunomodulation by an Adenylate Cyclase Activator, NKH477,in Vivoandin Vitro

Cited by 13 publications

References 0 publications

Prostaglandin E2 Inhibits IL-18-Induced ICAM-1 and B7.2 Expression Through EP2/EP4 Receptors in Human Peripheral Blood Mononuclear Cells

Prostaglandin E2 Inhibits IL-18-Induced ICAM-1 and B7.2 Expression Through EP2/EP4 Receptors in Human Peripheral Blood Mononuclear Cells

Cyclic AMP prolongs graft survival by suppressing apoptosis and inflammatory gene expression in acute cardiac allograft rejection

Antiproliferative effects of NKH477, a forskolin derivative, on cytokine profile in rat lung allografts

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