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Blood, 15 April 2007, Vol. 109, No. 8, pp. 3130-3131. This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Gordon, J. Articles by Barnes, N. M. Search for Related Content PubMed Articles by Gordon, J. Articles by Barnes, N. M. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY Comment on León-Ponte et al, page 3139 Serotonin: a real blast for T cells John Gordon, and Nicholas M. Barnes 1 UNIVERSITY OF BIRMINGHAM MEDICAL SCHOOL Mouse T lymphocytes unexpectedly produce the classic neurotransmitter serotonin, which—upon binding the constitutively expressed 5-HT7 Gs-coupled receptor-subtype—signals ERK1/2 phosphorylation and NFB activation to boost their stimulation. Serotonin/5-hydroxytryptamine (5-HT), often perceived as the brain's "happy chemical," is—increasingly—assuming a prominent role in immune regulation. In fact, this "neurotransmitter" is primarily a product of the periphery, with gut enterochromaffin cells the principal factories. Intestinal lymphocytes could certainly be exposed directly to their output, though platelets are typically proffered as the source of the monoamine within the immune system: these 5-HT–loaded reservoirs delivering their potent cargo at sights of inflammation and immunologic reactivity.1,2 In this issue of Blood, León-Ponte and colleagues not only consolidate serotonin's importance to T-cell activation but also tender a paradigm whereby the monoamine is provided by the immune cell itself. Critical to any outcome from 5-HT exposure—whether the source be autocrine or paracrine—is a capacity for target cells to sense the monoamine. This could be via the serotonin transporter (SERT) or one or more of 14 receptor subtypes (13 in rodents).1,2 Using reverse transcription–polymerase chain reaction (RT-PCR), the authors ruled out SERT and all but 3 receptor subtypes: only 5-HT1B, 5-HT2A, and 5-HT7 receptors remaining to deliver the 5-HT hit. While not excluding contributions from 5-HT1B and 5-HT2A receptors, the authors homed in on 5-HT7 as the major player: this 7-transmembrane domain G protein–coupled receptor (GPCR) assisted T-cell stimulation by promoting ERK1/2 phosphorylation and canonical NFB activation. Not only were the authors able to attenuate 5-HT–dependent change with a selective 5-HT7 receptor antagonist but, by using a 5-HT7 receptor agonist, were able to reverse otherwise defective T-cell stimulation arising as a consequence of having blocked tryptophan hydroxylase (TPH), the rate-limiting enzyme in the conversion of tryptophan to 5-HT. Tryptophan is also the catabolic substrate for indolamine-2,3-dioxygenase (IDO), and the relative abundance/activity of TPH, IDO, and, additionally, metabolizing monoamine oxidases (MAOs) could determine 5-HT output from immune cells. While the present study marks a significant advance, the authors themselves address seeming inconsistencies between this and isolated reports on the relative importance of individual 5-HT receptor subtypes to T-cell function, and rightly posit additional questions. Issues include strain and species differences, tissue and subset heterogeneity, and methodological concerns. Few studies have attempted such an extensive survey of an immune cell's 5-HT receptor repertoire as the one here. The table summarizes and compares the study's salient features with 3 others of merit: a pioneering study on rat splenocytes3 and, from Idzko and colleagues, separate analyses of receptor subtype distribution on human dendritic cells (Idzko et al4) and monocytes (Durk et al5). Of the discordant and common themes, the near-universal expression of 5-HT7 receptors—irrespective of cell type or animal species—is striking. A built-in knowledge of the pharmacology and signaling properties of 5-HT receptors (see table), driven by and gained largely through their contribution to CNS pathways, holds promise for the ready translation of 5-HT receptor therapeutics to immunology and hematology clinics once a more robust integration of their place in immune physiology—and pathology—has been secured. View this table: [in this window] [in a new window]   Reported expression of 5-HT receptor transcripts in immune cells. Synthesis of findings from studies by *León-Ponte et al in this issue of Blood and from Stefulj et al,3 Idzko et al,4 and Durk et al5 highlighting the repertoire of 5-HT receptor subtype of mRNA expressed in immune cells. R indicates resting; A, activated; I, immature; M, mature; Ion chan., ligand-gated ion channel; –, negative; +, strong signal; and ±, weak signal. 5-HT1B protein increased on activation. ¶Absent from mouse and rat. #Truncated transcript in human. Illustration by Frank Forney.   Footnotes The authors are directors and cofounders of Celentyx Ltd, a spinout company whose activities include the profiling of serotonergic compounds against immune cells. REFERENCES Meredith EJ, Chamba A, Holder MJ, et al. Close encounters of the monoamine kind: immune cells betray their nervous disposition. Immunology 2005; 115:289–295.[CrossRef][Medline] [Order article via Infotrieve] Gordon J and Barnes NM. Lymphocytes transport serotonin and dopamine: agony or ecstasy? Trends Immunol 2003; 24:438–443.[CrossRef][Medline] [Order article via Infotrieve] Stefulj J, Jernej B, Cicin-Sain L, et al. mRNA expression of serotonin receptors in cells of the immune tissues of the rat. Brain Behav Immun 2000; 14:219–224.[CrossRef][Medline] [Order article via Infotrieve] Idzko M, Panther E, Stratz C, et al. The serotoninergic receptors of human dendritic cells: identification and coupling to cytokine release. J Immunol 2004; 172:6011–6019.[Abstract/Free Full Text] Durk T, Panther E, Muller T, et al. 5-Hydroxytryptamine modulates cytokine and chemokine production in LPS-primed human monocytes via stimulation of different 5-HTR subtypes. Int Immunol 2005; 17:599–606.[Abstract/Free Full Text] CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Serotonin provides an accessory signal to enhance T-cell activation by signaling through the 5-HT7 receptor Matilde León-Ponte,, Gerard P. Ahern, and Peta J. O'Connell Blood 2007 109: 3139-3146. [Abstract] [Full Text] [PDF] This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Gordon, J. Articles by Barnes, N. M. Search for Related Content PubMed Articles by Gordon, J. Articles by Barnes, N. M. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?

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