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Christopher J. Paige - One of the best experts on this subject based on the ideXlab platform.
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Hemokinin-1 is an important mediator of endotoxin-induced acute airway inflammation in the mouse.
Peptides, 2014Co-Authors: Zsofia Hajna, Alexandra Berger, Christopher J. Paige, Eva Borbely, Laszlo Kereskai, Erika Pinter, Janos Szolcsanyi, Ágnes Kemény, Bálint Botz, Zsuzsanna HelyesAbstract:Abstract Objective Hemokinin-1, the newest tachykinin encoded by the preprotachykinin C (TAC4) gene, is predominatly produced by immune cells. Similarly to substance P, it has the greatest affinity to the tachykinin NK1 receptor, but has different binding site and signaling mechanisms. Furthermore, several recent data indicate the existence of a not yet identified own receptor and divergent non-NK1-mediated actions. Since there is no information on its functions in the airways, we investigated its role in endotoxin-induced pulmonary inflammation. Methods Acute pneumonitis was induced in TAC4 gene-deleted (TAC4 −/− ) mice compared to C57Bl/6 wildtypes by intranasal E. coli lipopolysaccharide (LPS). Airway responsiveness to inhaled carbachol was measured with unrestrained whole body plethysmography 24 h later. Semiquantitative histopathological scoring was performed; reactive oxygen species (ROS) production was measured with luminol bioluminescence, myeloperoxidase activity with spectrophotometry, and inflammatory cytokines with Luminex. Results All inflammatory parameters, such as histopathological alterations (perivascular edema, neutrophil/macrophage accumulation, goblet cell hyperplasia), myeloperoxidase activity, ROS production, as well as interleukin-1beta, interleukin-6, tumor necrosis factor alpha, monocyte chemoattractant protein-1 and keratinocyte chemoattractant concentrations were significantly diminished in the lung of TAC4 −/− mice. However, bronchial hyperreactivity similarly developed in both groups. Interestingly, in LPS-treated TAC4 −/− mouse lungs, bronchus-associated, large, follicle-like lymphoid structures developed. Conclusions We provide the first evidence that hemokinin-1 plays a crucial pro-inflammatory role in the lung by increasing inflammatory cell activities, and might also be a specific regulator of lymphocyte functions.
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Neurokinin-1 Receptor Signalling Impacts Bone Marrow Repopulation Efficiency
PloS one, 2013Co-Authors: Alexandra Berger, Catherine Frelin, Divya K. Shah, Patricia Benveniste, Robert Herrington, Norma P. Gerard, Juan Carlos Zúñiga-pflücker, Norman N. Iscove, Christopher J. PaigeAbstract:Tachykinins are a large group of neuropeptides with both central and peripheral activity. Despite the increasing number of studies reporting a growth supportive effect of tachykinin peptides in various in vitro stem cell systems, it remains unclear whether these findings are applicable in vivo. To determine how neurokinin-1 receptor (NK-1R) deficient hematopoietic stem cells would behave in a normal in vivo environment, we tested their reconstitution efficiency using competitive bone marrow repopulation assays. We show here that bone marrow taken from NK-1R deficient mice (Tacr1−/−) showed lineage specific B and T cell engraftment deficits compared to wild-type competitor bone marrow cells, providing evidence for an involvement of NK-1R signalling in adult hematopoiesis. Tachykinin knockout mice lacking the peptides SP and/or HK-1 (Tac1−/−, TAC4−/− and Tac1−/−/TAC4−/− mice) repopulated a lethally irradiated wild-type host with similar efficiency as competing wild-type bone marrow. The difference between peptide and receptor deficient mice indicates a paracrine and/or endocrine mechanism of action rather than autocrine signalling, as tachykinin peptides are supplied by the host environment.
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diminished pheromone induced sexual behavior in neurokinin 1 receptor deficient tacr1 mice
Genes Brain and Behavior, 2012Co-Authors: Alexandra Berger, Christopher J. Paige, Norma P. Gerard, Anne H Tran, J Dida, S Minkin, J YeomansAbstract:Studies in mice with targeted deletions of tachykinin genes suggest that tachykinins and their receptors influence emotional behaviors such as aggression, depression and anxiety. Here, we investigated whether TAC1- and TAC4-encoded peptides (substance P and hemokinin-1, respectively) and the neurokinin-1 receptor (NK-1R) are involved in the modulation of sexual behaviors. Male mice deficient for the NK-1R (TACR1 −/−) exhibited decreased exploration of female urine in contrast to C57BL/6 control mice and mice deficient for NK-1R ligands such as TAC1 −/−, TAC4 −/− and the newly generated TAC1 −/− /TAC4 −/− mice. In comparison to C57BL/6 mice, mounting frequency and duration were decreased in male TACR1 −/− mice, while mounting latency was increased. Decreased preference for sexual pheromones was also seen in female TACR1 −/− mice. Furthermore, administration of the NK-1R-antagonist L-703,606 decreased investigation of female urine by male C57BL/6 mice, suggesting an involvement of NK-1R in urine sniffing behavior. Our results provide evidence for the NK-1R in facilitating sexual approach behavior, as male TACR1 −/− mice exhibited blunted approach behavior toward females following the initial interaction compared with C57BL/6 mice. NK-1R signaling may therefore play an important role in pheromone-induced sexual behavior.
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targeted deletion of the tachykinin 4 gene TAC4 influences the early stages of b lymphocyte development
Blood, 2010Co-Authors: Alexandra Berger, Christopher J. Paige, Patricia Benveniste, Norman N. Iscove, Anne H Tran, Steven A. Corfe, Mary Barbara, Andrew Wakeham, Tak W. MakAbstract:Hemokinin-1 (HK-1), encoded by the TAC4 gene, is a tachykinin peptide that is predominantly expressed in non-neuronal cells, such as immune cells. We have disrupted the mouse TAC4 gene to obtain a better understanding of the actions of HK-1 during hematopoiesis. We demonstrate here that TAC4 −/− mice exhibit an increase of CD19+CD117+HSA+BP.1− “fraction B” pro-B cells in the bone marrow, whereas pre-B, immature, and mature B cells are within the normal range. We show that in vitro cultures derived from TAC4 −/− bone marrow, sorted “fraction B” pro-B cells or purified long-term reconstituting stem cells, contain significantly higher numbers of pro-B cells compared with controls, suggesting an inhibitory role for HK-1 on developing B cells. Supporting this idea, we show that addition of HK-1 to cultures established from long-term reconstituting stem cells and the newly described intermediate-term reconstituting stem cells leads to a significant decrease of de novo generated pro-B cells. Based on our studies, we postulate that HK-1 plays an inhibitory role in hematopoiesis, and we hypothesize that it may be part of the bone marrow microenvironment that supports and regulates the proliferation and differentiation of hematopoietic cells.
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Early B-cell factor regulates the expression of Hemokinin-1 in the olfactory epithelium and differentiating B lymphocytes.
Journal of Neuroimmunology, 2010Co-Authors: Anne H Tran, Alexandra Berger, Barbara L. Kee, Christopher J. PaigeAbstract:Hemokinin-1, encoded by the TAC4 gene, is a tachykinin most closely related to substance P. Previous studies have shown that TAC4 distinguishes itself from other tachykinins by its predominantly non-neuronal expression profile, particularly in cells of the immune system. Here we report for the first time that the highest levels of TAC4 expression are found in the olfactory epithelium. Furthermore, we identify olfactory neuron-specific transcription factor (Olf-1), also known as early B-cell factor (EBF), as a novel regulator of TAC4 expression. EBF present in the olfactory epithelium and in B cells binds to two sites in the TAC4 promoter and modulates expression in developing B cells. Our findings suggest a role for TAC4 in cell differentiation, and represent a regulatory bridge between the nervous system and the immune system.
Luz Candenas - One of the best experts on this subject based on the ideXlab platform.
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Autocrine regulation of human sperm motility by tachykinins.
Reproductive biology and endocrinology : RB&E, 2010Co-Authors: Francisco M. Pinto, Cristina G Ravina, Manuel Fernández-sánchez, Nerea Subirán, Antonio Cejudo-román, Jon Irazusta, Nicolas Garrido, Luz CandenasAbstract:Background: We examined the presence and function of tachykinins and the tachykinin-degrading enzymes neprilysin (NEP) and neprilysin-2 (NEP2) in human spermatozoa. Methods: Freshly ejaculated semen was collected from forty-eight normozoospermic human donors. We analyzed the expression of substance P, neurokinin A, neurokinin B, hemokinin-1, NEP and NEP2 in sperm cells by reversetranscriptase polymerase chain reaction (RT-PCR), western blot and immunocytochemistry assays and evaluated the effects of the neprilysin and neprilysin-2 inhibitor phosphoramidon on sperm motility in the absence and presence of tachykinin receptor-selective antagonists. Sperm motility was measured using WHO procedures or computerassisted sperm analysis (CASA). Results: The mRNAs of the genes that encode substance P/neurokinin A (TAC1), neurokinin B (TAC3), hemokinin-1 (TAC4), neprilysin (MME) and neprilysin-2 (MMEL1) were expressed in human sperm. Immunocytochemistry studies revealed that tachykinin and neprilysin proteins were present in spermatozoa and show specific and differential distributions. Phosphoramidon increased sperm progressive motility and its effects were reduced in the presence of the tachykinin receptor antagonists SR140333 (NK1 receptor-selective) and SR48968 (NK2 receptor-selective) but unmodified in the presence of SR142801 (NK3 receptor-selective). Conclusion: These data show that tachykinins are present in human spermatozoa and participate in the regulation of sperm motility. Tachykinin activity is regulated, at least in part, by neprilysins.
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Common variants of the neuropeptide expressing tachykinin genes and susceptibility to asthma: a case-control study.
Journal of neuroimmunology, 2010Co-Authors: Tilman E Klassert, Luz Candenas, Juan J Sánchez, Teresa A Almeida, Francisco Pinto, Orlando Acosta, Mariano HernándezAbstract:Since tachykinins appear to be involved in the pathogenesis of allergic asthma, we investigated a possible association between 28 single nucleotide polymorphisms of the tachykinin genes TAC1, TAC3 and TAC4, and asthma susceptibility. A case-control study was conducted on 102 patients and 100 healthy subjects from the Canary Islands (Spain). A significant association with asthma was observed for two SNPs: rs2291855 in the TAC3 gene conferring asthma protection (Odds ratio [OR]: 0.46; 95% Confidence Interval [CI]: 0.22-0.97; P=0.038), and rs4794068 in the TAC4 gene associated with an increased risk for asthma (OR: 1.94; 95% CI: 1.06-3.54; P=0.03). The present study represents a preliminary step in elucidating the association between tachykinin gene polymorphisms and asthma susceptibility.
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Common variants of the neuropeptide expressing tachykinin genes and susceptibility to asthma: A case–control study
Journal of Neuroimmunology, 2010Co-Authors: Tilman E Klassert, Francisco M. Pinto, Luz Candenas, Juan J Sánchez, Teresa A Almeida, Orlando Acosta, Mariano HernándezAbstract:Since tachykinins appear to be involved in the pathogenesis of allergic asthma, we investigated a possible association between 28 single nucleotide polymorphisms of the tachykinin genes TAC1, TAC3 and TAC4, and asthma susceptibility. A case-control study was conducted on 102 patients and 100 healthy subjects from the Canary Islands (Spain). A significant association with asthma was observed for two SNPs: rs2291855 in the TAC3 gene conferring asthma protection (Odds ratio [OR]: 0.46; 95% Confidence Interval [CI]: 0.22-0.97; P=0.038), and rs4794068 in the TAC4 gene associated with an increased risk for asthma (OR: 1.94; 95% CI: 1.06-3.54; P=0.03). The present study represents a preliminary step in elucidating the association between tachykinin gene polymorphisms and asthma susceptibility.
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Ovarian steroids regulate tachykinin and tachykinin receptor gene expression in the mouse uterus
Reproductive biology and endocrinology : RB&E, 2009Co-Authors: Francisco M. Pinto, Jocelyn N Pennefather, Eva N Patak, C. Oscar Pintado, Luz CandenasAbstract:Background: In the mouse uterus, pregnancy is accompanied by changes in tachykinin and tachykinin receptor gene expression and in the uterotonic effects of endogenous tachykinins. In this study we have investigated whether changes in tachykinin expression and responses are a result of changes in ovarian steroid levels. Methods: We quantified the mRNAs of tachykinins and tachykinin receptors in uteri from ovariectomized mice and studied their regulation in response to estrogen and progesterone using real-time quantitative RT-PCR. Early (3 h) and late (24 h) responses to estrogen were evaluated and the participation of the estrogen receptors (ER), ERalpha and ERbeta, was analyzed by treating mice with propylpyrazole triol, a selective ERalpha agonist, or diarylpropionitrile, a selective agonist of ERbeta. Results: All genes encoding tachykinins (Tac1, Tac2 and TAC4) and tachykinin receptors (Tacr1, Tacr2 and Tacr3) were expressed in uteri from ovariectomized mice. Estrogen increased Tac1 and Tacr1 mRNA after 3 h and decreased Tac1 and TAC4 expression after 24 h. Tac2 and Tacr3 mRNA levels were decreased by estrogen at both 3 and 24 h. Most effects of estrogen were also observed in animals treated with propylpyrazole triol. Progesterone treatment increased the levels of Tac2. Conclusion: These results show that the expression of tachykinins and their receptors in the mouse uterus is tightly and differentially regulated by ovarian steroids. Estrogen effects are mainly mediated by ERalpha supporting an essential role for this estrogen receptor in the regulation of the tachykinergic system in the mouse uterus.
Francisco M. Pinto - One of the best experts on this subject based on the ideXlab platform.
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Autocrine regulation of human sperm motility by tachykinins.
Reproductive biology and endocrinology : RB&E, 2010Co-Authors: Francisco M. Pinto, Cristina G Ravina, Manuel Fernández-sánchez, Nerea Subirán, Antonio Cejudo-román, Jon Irazusta, Nicolas Garrido, Luz CandenasAbstract:Background: We examined the presence and function of tachykinins and the tachykinin-degrading enzymes neprilysin (NEP) and neprilysin-2 (NEP2) in human spermatozoa. Methods: Freshly ejaculated semen was collected from forty-eight normozoospermic human donors. We analyzed the expression of substance P, neurokinin A, neurokinin B, hemokinin-1, NEP and NEP2 in sperm cells by reversetranscriptase polymerase chain reaction (RT-PCR), western blot and immunocytochemistry assays and evaluated the effects of the neprilysin and neprilysin-2 inhibitor phosphoramidon on sperm motility in the absence and presence of tachykinin receptor-selective antagonists. Sperm motility was measured using WHO procedures or computerassisted sperm analysis (CASA). Results: The mRNAs of the genes that encode substance P/neurokinin A (TAC1), neurokinin B (TAC3), hemokinin-1 (TAC4), neprilysin (MME) and neprilysin-2 (MMEL1) were expressed in human sperm. Immunocytochemistry studies revealed that tachykinin and neprilysin proteins were present in spermatozoa and show specific and differential distributions. Phosphoramidon increased sperm progressive motility and its effects were reduced in the presence of the tachykinin receptor antagonists SR140333 (NK1 receptor-selective) and SR48968 (NK2 receptor-selective) but unmodified in the presence of SR142801 (NK3 receptor-selective). Conclusion: These data show that tachykinins are present in human spermatozoa and participate in the regulation of sperm motility. Tachykinin activity is regulated, at least in part, by neprilysins.
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Common variants of the neuropeptide expressing tachykinin genes and susceptibility to asthma: A case–control study
Journal of Neuroimmunology, 2010Co-Authors: Tilman E Klassert, Francisco M. Pinto, Luz Candenas, Juan J Sánchez, Teresa A Almeida, Orlando Acosta, Mariano HernándezAbstract:Since tachykinins appear to be involved in the pathogenesis of allergic asthma, we investigated a possible association between 28 single nucleotide polymorphisms of the tachykinin genes TAC1, TAC3 and TAC4, and asthma susceptibility. A case-control study was conducted on 102 patients and 100 healthy subjects from the Canary Islands (Spain). A significant association with asthma was observed for two SNPs: rs2291855 in the TAC3 gene conferring asthma protection (Odds ratio [OR]: 0.46; 95% Confidence Interval [CI]: 0.22-0.97; P=0.038), and rs4794068 in the TAC4 gene associated with an increased risk for asthma (OR: 1.94; 95% CI: 1.06-3.54; P=0.03). The present study represents a preliminary step in elucidating the association between tachykinin gene polymorphisms and asthma susceptibility.
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Ovarian steroids regulate tachykinin and tachykinin receptor gene expression in the mouse uterus
Reproductive biology and endocrinology : RB&E, 2009Co-Authors: Francisco M. Pinto, Jocelyn N Pennefather, Eva N Patak, C. Oscar Pintado, Luz CandenasAbstract:Background: In the mouse uterus, pregnancy is accompanied by changes in tachykinin and tachykinin receptor gene expression and in the uterotonic effects of endogenous tachykinins. In this study we have investigated whether changes in tachykinin expression and responses are a result of changes in ovarian steroid levels. Methods: We quantified the mRNAs of tachykinins and tachykinin receptors in uteri from ovariectomized mice and studied their regulation in response to estrogen and progesterone using real-time quantitative RT-PCR. Early (3 h) and late (24 h) responses to estrogen were evaluated and the participation of the estrogen receptors (ER), ERalpha and ERbeta, was analyzed by treating mice with propylpyrazole triol, a selective ERalpha agonist, or diarylpropionitrile, a selective agonist of ERbeta. Results: All genes encoding tachykinins (Tac1, Tac2 and TAC4) and tachykinin receptors (Tacr1, Tacr2 and Tacr3) were expressed in uteri from ovariectomized mice. Estrogen increased Tac1 and Tacr1 mRNA after 3 h and decreased Tac1 and TAC4 expression after 24 h. Tac2 and Tacr3 mRNA levels were decreased by estrogen at both 3 and 24 h. Most effects of estrogen were also observed in animals treated with propylpyrazole triol. Progesterone treatment increased the levels of Tac2. Conclusion: These results show that the expression of tachykinins and their receptors in the mouse uterus is tightly and differentially regulated by ovarian steroids. Estrogen effects are mainly mediated by ERalpha supporting an essential role for this estrogen receptor in the regulation of the tachykinergic system in the mouse uterus.
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A role for tachykinins in the regulation of human sperm motility
Human reproduction (Oxford England), 2007Co-Authors: Cristina G Ravina, Francisco M. Pinto, M. Seda, A. Orea, Manuel Fernández-sánchez, C.o. Pintado, M. Luz CandenasAbstract:BACKGROUND: Tachykinins and tachykinin receptors are widely distributed in the male reproductive tract and appear to be involved in reproduction. However, the function and expression of tachykinins and their receptors in human spermatozoa remain poorly studied. We analysed the effects of tachykinins on sperm motility and characterized the population of tachykinin receptors in human spermatozoa. METHODS AND RESULTS: Motility analysis was performed following World Health Organization guidelines and we found that substance P (SP), human hemokinin-1 (hHK-1), neurokinin A (NKA) and neurokinin B (NKB) produced concentration-dependent increases in sperm progressive motility. The effects of tachykinins were antagonized by the NK 1 receptor-selective antagonist SR 140333, the NK 2 receptor-selective antagonist, SR 48968 and, to a lesser extent, also by the NK 3 receptor-selective antagonist SR 142801. Immunocytochemistry studies showed expression of the NK 1 , NK 2 and NK 3 tachykinin receptor proteins in spermatozoa with different major sites of localization for each receptor. Western blot analysis confirmed the presence of tachykinin receptors in sperm cell homogenates. RT-PCR demonstrated expression of the genes that encode SP/NKA (TACT), NKB (TAC3) and hHK-1 (TAC4) but not the genes TACR1, TACR2 and TACR3 encoding NK 1 , NK 2 and NK 3 receptors, respectively. CONCLUSIONS: These results show for the first time that the NK 1 , NK 2 and NK 3 tachykinin receptor proteins are present in human spermatozoa. Our findings suggest that tachykinins, probably acting through these three tachykinin receptors, play a role in the regulation of human sperm motility.
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Functional and Molecular Characterization of Tachykinins and Tachykinin Receptors in the Mouse Uterus
Biology of reproduction, 2005Co-Authors: Eva N Patak, Nigel Page, Francisco M. Pinto, Jocelyn N Pennefather, Margot E Story, C. Oscar Pintado, Anna J Fleming, M. Luz CandenasAbstract:The aim of this study was to analyze the function and expression of tachykinins, tachykinin receptors, and neprilysin (NEP) in the mouse uterus. A previous study showed that the uterotonic effects of substance P (SP), neurokinin A (NKA), and neurokinin B (NKB) in estrogen-treated mice were mainly mediated by the tachykinin NK1 receptor. In the present work, further contractility studies were undertaken to determine the nature of the receptors mediating responses to tachykinins in uteri of late pregnant mice. Endpoint and real-time quantitative RT-PCR were used to analyze the expression of the genes that encode the tachykinins SP/NKA, NKB, and hemokinin-1 (HK-1) (Tac1, Tac2, and TAC4); and the genes that encode tachykinin NK1 (Tacr1), NK2 (Tacr2), and NK3 (Tacr3) receptors in uteri from pregnant and nonpregnant mice. The data show that the mRNAs of tachykinins (particularly NKB and HK-1), tachykinin receptors, and NEP are locally expressed in the mouse uterus, and their expression changes during the estrous cycle and during pregnancy. The tachykinin NK1 receptor is the predominant tachykinin receptor in the nonpregnant and early pregnant mouse and may mediate tachykinin-induced uterine contractions in the nonpregnant mouse. The tachykinin NK2 receptor is predominant in the late pregnant mouse and is the main receptor mediating uterotonic responses to tachykinins at late pregnancy. The tachykinin NK3 receptor is expressed in considerable amounts only in uteri from nonpregnant diestrous animals, and its physiological significance remains to be clarified.
Alexandra Berger - One of the best experts on this subject based on the ideXlab platform.
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Hemokinin-1 is an important mediator of endotoxin-induced acute airway inflammation in the mouse.
Peptides, 2014Co-Authors: Zsofia Hajna, Alexandra Berger, Christopher J. Paige, Eva Borbely, Laszlo Kereskai, Erika Pinter, Janos Szolcsanyi, Ágnes Kemény, Bálint Botz, Zsuzsanna HelyesAbstract:Abstract Objective Hemokinin-1, the newest tachykinin encoded by the preprotachykinin C (TAC4) gene, is predominatly produced by immune cells. Similarly to substance P, it has the greatest affinity to the tachykinin NK1 receptor, but has different binding site and signaling mechanisms. Furthermore, several recent data indicate the existence of a not yet identified own receptor and divergent non-NK1-mediated actions. Since there is no information on its functions in the airways, we investigated its role in endotoxin-induced pulmonary inflammation. Methods Acute pneumonitis was induced in TAC4 gene-deleted (TAC4 −/− ) mice compared to C57Bl/6 wildtypes by intranasal E. coli lipopolysaccharide (LPS). Airway responsiveness to inhaled carbachol was measured with unrestrained whole body plethysmography 24 h later. Semiquantitative histopathological scoring was performed; reactive oxygen species (ROS) production was measured with luminol bioluminescence, myeloperoxidase activity with spectrophotometry, and inflammatory cytokines with Luminex. Results All inflammatory parameters, such as histopathological alterations (perivascular edema, neutrophil/macrophage accumulation, goblet cell hyperplasia), myeloperoxidase activity, ROS production, as well as interleukin-1beta, interleukin-6, tumor necrosis factor alpha, monocyte chemoattractant protein-1 and keratinocyte chemoattractant concentrations were significantly diminished in the lung of TAC4 −/− mice. However, bronchial hyperreactivity similarly developed in both groups. Interestingly, in LPS-treated TAC4 −/− mouse lungs, bronchus-associated, large, follicle-like lymphoid structures developed. Conclusions We provide the first evidence that hemokinin-1 plays a crucial pro-inflammatory role in the lung by increasing inflammatory cell activities, and might also be a specific regulator of lymphocyte functions.
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Neurokinin-1 Receptor Signalling Impacts Bone Marrow Repopulation Efficiency
PloS one, 2013Co-Authors: Alexandra Berger, Catherine Frelin, Divya K. Shah, Patricia Benveniste, Robert Herrington, Norma P. Gerard, Juan Carlos Zúñiga-pflücker, Norman N. Iscove, Christopher J. PaigeAbstract:Tachykinins are a large group of neuropeptides with both central and peripheral activity. Despite the increasing number of studies reporting a growth supportive effect of tachykinin peptides in various in vitro stem cell systems, it remains unclear whether these findings are applicable in vivo. To determine how neurokinin-1 receptor (NK-1R) deficient hematopoietic stem cells would behave in a normal in vivo environment, we tested their reconstitution efficiency using competitive bone marrow repopulation assays. We show here that bone marrow taken from NK-1R deficient mice (Tacr1−/−) showed lineage specific B and T cell engraftment deficits compared to wild-type competitor bone marrow cells, providing evidence for an involvement of NK-1R signalling in adult hematopoiesis. Tachykinin knockout mice lacking the peptides SP and/or HK-1 (Tac1−/−, TAC4−/− and Tac1−/−/TAC4−/− mice) repopulated a lethally irradiated wild-type host with similar efficiency as competing wild-type bone marrow. The difference between peptide and receptor deficient mice indicates a paracrine and/or endocrine mechanism of action rather than autocrine signalling, as tachykinin peptides are supplied by the host environment.
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diminished pheromone induced sexual behavior in neurokinin 1 receptor deficient tacr1 mice
Genes Brain and Behavior, 2012Co-Authors: Alexandra Berger, Christopher J. Paige, Norma P. Gerard, Anne H Tran, J Dida, S Minkin, J YeomansAbstract:Studies in mice with targeted deletions of tachykinin genes suggest that tachykinins and their receptors influence emotional behaviors such as aggression, depression and anxiety. Here, we investigated whether TAC1- and TAC4-encoded peptides (substance P and hemokinin-1, respectively) and the neurokinin-1 receptor (NK-1R) are involved in the modulation of sexual behaviors. Male mice deficient for the NK-1R (TACR1 −/−) exhibited decreased exploration of female urine in contrast to C57BL/6 control mice and mice deficient for NK-1R ligands such as TAC1 −/−, TAC4 −/− and the newly generated TAC1 −/− /TAC4 −/− mice. In comparison to C57BL/6 mice, mounting frequency and duration were decreased in male TACR1 −/− mice, while mounting latency was increased. Decreased preference for sexual pheromones was also seen in female TACR1 −/− mice. Furthermore, administration of the NK-1R-antagonist L-703,606 decreased investigation of female urine by male C57BL/6 mice, suggesting an involvement of NK-1R in urine sniffing behavior. Our results provide evidence for the NK-1R in facilitating sexual approach behavior, as male TACR1 −/− mice exhibited blunted approach behavior toward females following the initial interaction compared with C57BL/6 mice. NK-1R signaling may therefore play an important role in pheromone-induced sexual behavior.
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targeted deletion of the tachykinin 4 gene TAC4 influences the early stages of b lymphocyte development
Blood, 2010Co-Authors: Alexandra Berger, Christopher J. Paige, Patricia Benveniste, Norman N. Iscove, Anne H Tran, Steven A. Corfe, Mary Barbara, Andrew Wakeham, Tak W. MakAbstract:Hemokinin-1 (HK-1), encoded by the TAC4 gene, is a tachykinin peptide that is predominantly expressed in non-neuronal cells, such as immune cells. We have disrupted the mouse TAC4 gene to obtain a better understanding of the actions of HK-1 during hematopoiesis. We demonstrate here that TAC4 −/− mice exhibit an increase of CD19+CD117+HSA+BP.1− “fraction B” pro-B cells in the bone marrow, whereas pre-B, immature, and mature B cells are within the normal range. We show that in vitro cultures derived from TAC4 −/− bone marrow, sorted “fraction B” pro-B cells or purified long-term reconstituting stem cells, contain significantly higher numbers of pro-B cells compared with controls, suggesting an inhibitory role for HK-1 on developing B cells. Supporting this idea, we show that addition of HK-1 to cultures established from long-term reconstituting stem cells and the newly described intermediate-term reconstituting stem cells leads to a significant decrease of de novo generated pro-B cells. Based on our studies, we postulate that HK-1 plays an inhibitory role in hematopoiesis, and we hypothesize that it may be part of the bone marrow microenvironment that supports and regulates the proliferation and differentiation of hematopoietic cells.
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Early B-cell factor regulates the expression of Hemokinin-1 in the olfactory epithelium and differentiating B lymphocytes.
Journal of Neuroimmunology, 2010Co-Authors: Anne H Tran, Alexandra Berger, Barbara L. Kee, Christopher J. PaigeAbstract:Hemokinin-1, encoded by the TAC4 gene, is a tachykinin most closely related to substance P. Previous studies have shown that TAC4 distinguishes itself from other tachykinins by its predominantly non-neuronal expression profile, particularly in cells of the immune system. Here we report for the first time that the highest levels of TAC4 expression are found in the olfactory epithelium. Furthermore, we identify olfactory neuron-specific transcription factor (Olf-1), also known as early B-cell factor (EBF), as a novel regulator of TAC4 expression. EBF present in the olfactory epithelium and in B cells binds to two sites in the TAC4 promoter and modulates expression in developing B cells. Our findings suggest a role for TAC4 in cell differentiation, and represent a regulatory bridge between the nervous system and the immune system.
Anne H Tran - One of the best experts on this subject based on the ideXlab platform.
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diminished pheromone induced sexual behavior in neurokinin 1 receptor deficient tacr1 mice
Genes Brain and Behavior, 2012Co-Authors: Alexandra Berger, Christopher J. Paige, Norma P. Gerard, Anne H Tran, J Dida, S Minkin, J YeomansAbstract:Studies in mice with targeted deletions of tachykinin genes suggest that tachykinins and their receptors influence emotional behaviors such as aggression, depression and anxiety. Here, we investigated whether TAC1- and TAC4-encoded peptides (substance P and hemokinin-1, respectively) and the neurokinin-1 receptor (NK-1R) are involved in the modulation of sexual behaviors. Male mice deficient for the NK-1R (TACR1 −/−) exhibited decreased exploration of female urine in contrast to C57BL/6 control mice and mice deficient for NK-1R ligands such as TAC1 −/−, TAC4 −/− and the newly generated TAC1 −/− /TAC4 −/− mice. In comparison to C57BL/6 mice, mounting frequency and duration were decreased in male TACR1 −/− mice, while mounting latency was increased. Decreased preference for sexual pheromones was also seen in female TACR1 −/− mice. Furthermore, administration of the NK-1R-antagonist L-703,606 decreased investigation of female urine by male C57BL/6 mice, suggesting an involvement of NK-1R in urine sniffing behavior. Our results provide evidence for the NK-1R in facilitating sexual approach behavior, as male TACR1 −/− mice exhibited blunted approach behavior toward females following the initial interaction compared with C57BL/6 mice. NK-1R signaling may therefore play an important role in pheromone-induced sexual behavior.
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targeted deletion of the tachykinin 4 gene TAC4 influences the early stages of b lymphocyte development
Blood, 2010Co-Authors: Alexandra Berger, Christopher J. Paige, Patricia Benveniste, Norman N. Iscove, Anne H Tran, Steven A. Corfe, Mary Barbara, Andrew Wakeham, Tak W. MakAbstract:Hemokinin-1 (HK-1), encoded by the TAC4 gene, is a tachykinin peptide that is predominantly expressed in non-neuronal cells, such as immune cells. We have disrupted the mouse TAC4 gene to obtain a better understanding of the actions of HK-1 during hematopoiesis. We demonstrate here that TAC4 −/− mice exhibit an increase of CD19+CD117+HSA+BP.1− “fraction B” pro-B cells in the bone marrow, whereas pre-B, immature, and mature B cells are within the normal range. We show that in vitro cultures derived from TAC4 −/− bone marrow, sorted “fraction B” pro-B cells or purified long-term reconstituting stem cells, contain significantly higher numbers of pro-B cells compared with controls, suggesting an inhibitory role for HK-1 on developing B cells. Supporting this idea, we show that addition of HK-1 to cultures established from long-term reconstituting stem cells and the newly described intermediate-term reconstituting stem cells leads to a significant decrease of de novo generated pro-B cells. Based on our studies, we postulate that HK-1 plays an inhibitory role in hematopoiesis, and we hypothesize that it may be part of the bone marrow microenvironment that supports and regulates the proliferation and differentiation of hematopoietic cells.
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Early B-cell factor regulates the expression of Hemokinin-1 in the olfactory epithelium and differentiating B lymphocytes.
Journal of Neuroimmunology, 2010Co-Authors: Anne H Tran, Alexandra Berger, Barbara L. Kee, Christopher J. PaigeAbstract:Hemokinin-1, encoded by the TAC4 gene, is a tachykinin most closely related to substance P. Previous studies have shown that TAC4 distinguishes itself from other tachykinins by its predominantly non-neuronal expression profile, particularly in cells of the immune system. Here we report for the first time that the highest levels of TAC4 expression are found in the olfactory epithelium. Furthermore, we identify olfactory neuron-specific transcription factor (Olf-1), also known as early B-cell factor (EBF), as a novel regulator of TAC4 expression. EBF present in the olfactory epithelium and in B cells binds to two sites in the TAC4 promoter and modulates expression in developing B cells. Our findings suggest a role for TAC4 in cell differentiation, and represent a regulatory bridge between the nervous system and the immune system.
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Targeted deletion of the tachykinin 4 gene (TAC4-/-) influences the early stages of B lymphocyte development.
Blood, 2010Co-Authors: Alexandra Berger, Patricia Benveniste, Norman N. Iscove, Anne H Tran, Steven A. Corfe, Mary Barbara, Andrew Wakeham, Tak W. Mak, Christopher J. PaigeAbstract:Hemokinin-1 (HK-1), encoded by the TAC4 gene, is a tachykinin peptide that is predominantly expressed in non-neuronal cells, such as immune cells. We have disrupted the mouse TAC4 gene to obtain a better understanding of the actions of HK-1 during hematopoiesis. We demonstrate here that TAC4 −/− mice exhibit an increase of CD19+CD117+HSA+BP.1− “fraction B” pro-B cells in the bone marrow, whereas pre-B, immature, and mature B cells are within the normal range. We show that in vitro cultures derived from TAC4 −/− bone marrow, sorted “fraction B” pro-B cells or purified long-term reconstituting stem cells, contain significantly higher numbers of pro-B cells compared with controls, suggesting an inhibitory role for HK-1 on developing B cells. Supporting this idea, we show that addition of HK-1 to cultures established from long-term reconstituting stem cells and the newly described intermediate-term reconstituting stem cells leads to a significant decrease of de novo generated pro-B cells. Based on our studies, we postulate that HK-1 plays an inhibitory role in hematopoiesis, and we hypothesize that it may be part of the bone marrow microenvironment that supports and regulates the proliferation and differentiation of hematopoietic cells.
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Regulatory mechanisms in the differential expression of Hemokinin-1.
Neuropeptides, 2008Co-Authors: Anne H Tran, Alexandra Berger, Christopher J. PaigeAbstract:Abstract Hemokinin-1, encoded by the TAC4 gene, is the most recent addition to the tachykinin family. Although most closely related to the neuropeptide Substance P, Hemokinin-1 distinguishes itself from other tachykinins by its predominantly non-neuronal expression pattern. Its expression in T and B lymphocytes, macrophages, and dendritic cells points to an important role for Hemokinin-1 in the immune system. To seek reasons for its preferential expression in the immune system and ultimately to provide clues to its function, we investigated the molecular mechanisms driving the differential expression pattern of this unique tachykinin. Our study provides the first analysis of the promoter region of the TAC4 gene, which reveals regulatory mechanism different from the Substance P promoter. We demonstrate for the first time that Hemokinin-1 initiates transcription from multiple start sites through a TATA-less promoter. Conservation of the 5′ non-coding region indicates the importance of the upstream regulatory region in directing expression of Hemokinin-1 in specific cell types, during cell differentiation and activation. Furthermore, NFκB, a transcription factor important in the activation of immune cells was shown to be involved in promoting increased TAC4 transcription during PMA induction of a T cell line. Our studies reveal that Hemokinin-1 is regulated by a unique transcription regulation system that likely governs its differential expression pattern and suggests a role for Hemokinin-1 distinct from Substance P .
