Induction of Indefinite Survival of Fully Mismatched Cardiac Allografts and Generation of Regulatory Cells by Sarpogrelate Hydrochloride

Akiyoshi, Takeshi; Zhang, Qi; Inoue, Fumihiko; Aramaki, Osamu; Hatano, Minoru; Shimazu, Motohide; Kitajima, Masaki; Shirasugi, Nozomu; Niimi, Masanori

doi:10.1097/01.tp.0000233870.54297.9a

Cited by 27 publications

(15 citation statements)

References 35 publications

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“…Inoue et al (2011) [17] showed that a 5-HT 2A agonist enhanced Concavalin-A induced activation whereas a 5-HT 2A antagonist blocked T-cell receptor mediated interleukin-2 and interferon-gamma production. Consistent with these data, Akiyoshi et al (2006) [18] showed that treatment with a 5-HT 2A antagonist enhanced the survival of cardiac allograft in mice.…”

Section: -Ht and Adaptive Immunitymentioning

confidence: 71%

5-HT and the immune system

Ahern

2011

Current Opinion in Pharmacology

205

163

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The classical neurotransmitter, serotonin (5-HT), plays an important role outside of the central nervous system in immune signaling. Here I review recent studies describing 5-HT uptake in dendritic cells and B lymphocytes, 5-HT synthesis in T lymphocytes, and the role of specific 5-HT receptor subtypes in innate and adaptive immune cells. Furthermore, a recent paper describing the immune phenotype of 5-HT deficient mice is discussed.

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Section: -Ht and Adaptive Immunitymentioning

confidence: 71%

5-HT and the immune system

Ahern

2011

Current Opinion in Pharmacology

205

163

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“…Furthermore, the mRNA of 5-HT2A, HT 4 and HT 7 receptor could be produced in activated T cells [6]. Moreover, selective 5-HT2A receptor inhibitor, sarpogrelate, induced longer survival of cardiac allografts in mice [7].…”

Section: Introductionmentioning

confidence: 98%

“…Of these15 receptors, signaling via 5-HT2A receptor (5-HT2AR) is important for regulation of the modulation of mood and perception in the central nervous system and of vasoconstriction and platelets aggregation in the periphery [4]. Increasing body of evidence suggests that this bioactive amine and its 5-HT2AR, in addition to these described activities, might also contribute to the immune system [5][6][7][8]. Prior to the classification of 5-HT2 receptor subtype [9], there had been some reports indicating that 5-HT could be a potent stimulator in T cell activation [10][11][12][13] although it was unclear which subtype of receptor mediated this activity.…”

Section: Introductionmentioning

confidence: 98%

Regulation of antigen-specific CTL and Th1 cell activation through 5-Hydroxytryptamine 2A receptor

Inoue

Okazaki

Kitazono

et al. 2011

International Immunopharmacology

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“…However, the role of 5-HT 2A receptors in inflammatory processes is unclear, with only a very few published and inconsistent reports. Some studies report that blockade of 5-HT 2A receptor function with the selective antagonist sarpogrelate can decrease expression of proinflammatory markers (Marconi et al, 2003;Akiyoshi et al, 2006), whereas others indicate that sarpogrelate can increase expression of proinflammatory markers (Ito et al, 2000). Cloëz-Tayarani et al (2003) have alleged that the 5-HT 2 receptor-specific agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) represses interleukin (IL)-1␤ expression and production of tumor necrosis factor-␣ (TNF-␣) through 5-HT 2A receptor activation.…”

mentioning

confidence: 99%

Serotonin 5-Hydroxytryptamine2A Receptor Activation Suppresses Tumor Necrosis Factor-α-Induced Inflammation with Extraordinary Potency

Yu¹,

Becnel²,

Zerfaoui³

et al. 2008

The Journal of Pharmacology and Experimental Therapeutics

172

129

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The G protein-coupled serotonin 5-hydroxytryptamine (5-HT) 2A receptor is primarily recognized for its role in brain neurotransmission, where it mediates a wide variety of functions, including certain aspects of cognition. However, there is significant expression of this receptor in peripheral tissues, where its importance is largely unknown. We have now discovered that activation of 5-HT 2A receptors in primary aortic smooth muscle cells provides a previously unknown and extremely potent inhibition of tumor necrosis factor (TNF)-␣-mediated inflammation. 5-HT 2A receptor stimulation with the agonist (R)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane [(R)-DOI] rapidly inhibits a variety of TNF-␣-mediated proinflammatory markers, including intracellular adhesion molecule 1 (ICAM-1), vascular adhesion molecule 1 (VCAM-1), and interleukin (IL)-6 gene expression, nitric-oxide synthase activity, and nuclear translocation of nuclear factor B, with IC 50 values of only 10 to 20 pM.It is significant that proinflammatory markers can also be inhibited by (R)-DOI hours after treatment with TNF-␣. With the exception of a few natural toxins, no current drugs or small molecule therapeutics demonstrate a comparable potency for any physiological effect. TNF-␣-mediated inflammatory pathways have been strongly implicated in a number of diseases, including atherosclerosis, rheumatoid arthritis, psoriasis, type II diabetes, depression, schizophrenia, and Alzheimer's disease. Our results indicate that activation of 5-HT 2A receptors represents a novel, and extraordinarily potent, potential therapeutic avenue for the treatment of disorders involving TNF-␣-mediated inflammation. Note that because (R)-DOI can significantly inhibit the effects of TNF-␣ many hours after the administration of TNF-␣, potential therapies could be aimed not only at preventing inflammation but also treating inflammatory injury that has already occurred or is ongoing.Serotonin, 5-hydroxytryptamine (5-HT), is a small monoamine molecule primarily known for its role as a neurotransmitter. Within the brain, it modulates a variety of behaviors including cognition, mood, aggression, mating, feeding, and sleep . These behaviors are mediated through interactions at seven different receptor families (5-HT 1-7 ) comprised of 14 distinct subtypes . Each of these are G protein-coupled receptors, with the exception of the 5-HT 3 receptor, which is a ligandgated ion channel. Of all the serotonin receptors, the 5-HT 2A receptor, which is known to primarily couple to the G␣q effector pathway (Roth et al., 1986), has been the one most closely linked to complex behaviors. There is a high level of expression within the frontal cortex, with significant localization to the apical dendrites of cortical pyramidal cells (Willins et al., 1997), and further expression at lower levels PKC, protein kinase C; Gö 6976, 5,6,7,pyrrolo [3,4-c]carbazole-12-propanenitrile; PMA, phorbol 12-myristate 13-acetate; F-22, fragment 6 -22; LA-SS-Az, (2ЈS,4ЈS)-(ϩ)-9,10-didehydro-6-methylergoli...

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Induction of Indefinite Survival of Fully Mismatched Cardiac Allografts and Generation of Regulatory Cells by Sarpogrelate Hydrochloride

Abstract: SH induced indefinite survival of fully allogeneic cardiac allografts, generated CD4 regulatory cells, inhibited ICAM-1 expression in the allografts, and upregulated IL-4 and IL-10 production.

Cited by 27 publications

References 35 publications

5-HT and the immune system

5-HT and the immune system

Regulation of antigen-specific CTL and Th1 cell activation through 5-Hydroxytryptamine 2A receptor

Serotonin 5-Hydroxytryptamine2A Receptor Activation Suppresses Tumor Necrosis Factor-α-Induced Inflammation with Extraordinary Potency

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