Cyclic AMP concentrations in dendritic cells induce and regulate Th2 immunity and allergic asthma

The inductive role of dendritic cells (DC) in Th2 differentiation has not been fully defined. We addressed this gap in knowledge by focusing on signaling events mediated by the heterotrimeric GTP binding proteins Gαs, and Gαi, which respectively stimulate and inhibit the activation of adenylyl cyclases and the synthesis of cAMP. We show here that deletion of Gnas, the gene that encodes Gαs in mouse CD11c+ cells (GnasΔCD11c mice), and the accompanying decrease in cAMP provoke Th2 polarization and yields a prominent allergic phenotype, whereas increases in cAMP inhibit these responses. The effects of cAMP on DC can be demonstrated in vitro and in vivo and are mediated via PKA. Certain gene products made by GnasΔCD11c DC affect the Th2 bias. These findings imply that G protein-coupled receptors, the physiological regulators of Gαs and Gαi activation and cAMP formation, act via PKA to regulate Th bias in DC and in turn, Th2-mediated immunopathologies.

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Negative control of basophil expansion by IRF-2 critical for the regulation of Th1/Th2 balance

Blood ◽

10.1182/blood-2005-04-1344 ◽

2005 ◽

Vol 106 (6) ◽

pp. 2011-2017 ◽

Cited By ~ 79

Author(s):

Shigeaki Hida ◽

Masumi Tadachi ◽

Takashi Saito ◽

Shinsuke Taki

Keyword(s):

Negative Control ◽

Interleukin 4 ◽

Th2 Polarization ◽

Kit Gene ◽

Th2 Development ◽

Neutral Conditions ◽

Th2 Differentiation

Abstract Although basophils are known to produce interleukin 4 (IL-4), the roles of these cells have been documented only in mice infected with parasites or in the effector phase of allergic inflammations. Here we show that naive mice lacking the transcription factor, interferon regulatory factor 2 (IRF-2), exhibited signal transducer and activator of transcription 6 (Stat6)–independent expansion of basophils in the periphery. IRF-2 appeared to act autonomously in the cells to negatively regulate the expansion of, but not cytokine production by, basophils. Spontaneous Th2 polarization of CD4+ T cells was observed in these mice and the genetic reduction of basophil numbers by mutating the Kit gene abolished such a polarization in vivo. We also found that both basophils and IL-4 derived from them were indeed essential for Th2 development under neutral conditions in vitro. Furthermore, neutralization of IL-3 abolished IL-4 production by basophils during Th1/Th2 differentiation cultures and subsequent Th2 development. These results indicated that basophils acted as a cellular converter to turn the neutral IL-3 into the Th2-inducing IL-4 during the initiation of Th1/Th2 differentiation. Thus, the negative regulatory role of IRF-2 on the basophil population size is critically important for preventing excess Th2 polarization and the Th1/Th2 balance in naive animals.

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A Review on Melatonin’s Effects in Cancer: Potential Mechanisms

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520617666171121120223 ◽

2018 ◽

Vol 18 (7) ◽

pp. 985-992 ◽

Cited By ~ 3

Author(s):

Aysegul Hanikoglu ◽

Ertan Kucuksayan ◽

Rana Cagla Akduman ◽

Tomris Ozben

Keyword(s):

Systematic Review ◽

Antioxidant Activity ◽

Membrane Receptors ◽

Cancer Development ◽

Secretory Product ◽

Prevention And Treatment ◽

G Protein Coupled

This systematic review aims to elucidate the role of melatonin (N-acetyl-5-metoxy-tryptamine) (MLT) in the prevention and treatment of cancer. MLT is a pineal gland secretory product, an evolutionarily highly conserved molecule; it is also an antioxidant and an impressive protector of mitochondrial bioenergetic activity. MLT is characterized by an ample range of activities, modulating the physiology and molecular biology of the cell. Its physiological functions relate principally to the interaction of G Protein-Coupled MT1 and MT2 trans-membrane receptors (GPCRs), a family of guanidine triphosphate binding proteins. MLT has been demonstrated to suppress the growth of various tumours both, in vivo and in vitro. In this review, we analyze in depth, the antioxidant activity of melatonin, aiming to illustrate the cancer treatment potential of the molecule, by limiting or reversing the changes occurring during cancer development and growth.

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Regulation of nephron water and electrolyte transport by adenylyl cyclases

AJP Renal Physiology ◽

10.1152/ajprenal.00656.2013 ◽

2014 ◽

Vol 306 (7) ◽

pp. F701-F709 ◽

Cited By ~ 13

Author(s):

Timo Rieg ◽

Donald E. Kohan

Keyword(s):

Hormonal Regulation ◽

Electrolyte Transport ◽

Adenylyl Cyclases ◽

Disease Pathogenesis ◽

Membrane Bound ◽

G Protein Coupled ◽

Camp Formation ◽

Distinct Membrane ◽

Genetically Modified Animals

Adenylyl cyclases (AC) catalyze formation of cAMP, a critical component of G protein-coupled receptor signaling. So far, nine distinct membrane-bound AC isoforms (AC1-9) and one soluble AC (sAC) have been identified and, except for AC8, all of them are expressed in the kidney. While the role of ACs in renal cAMP formation is well established, we are just beginning to understand the function of individual AC isoforms, particularly with regard to hormonal regulation of transporter and channel phosphorylation, membrane abundance, and trafficking. This review focuses on the role of different AC isoforms in regulating renal water and electrolyte transport in health as well as potential pathological implications of disordered AC isoform function. In particular, we focus on modulation of transporter and channel abundance, activity, and phosphorylation, with an emphasis on studies employing genetically modified animals. As will be described, it is now evident that specific AC isoforms can exert unique effects in the kidney that may have important implications in our understanding of normal physiology as well as disease pathogenesis.

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In Vivo Role of Dendritic Cells in a Murine Model of Pulmonary Cryptococcosis

Infection and Immunity ◽

10.1128/iai.00317-06 ◽

2006 ◽

Vol 74 (7) ◽

pp. 3817-3824 ◽

Cited By ~ 58

Author(s):

Karen L. Wozniak ◽

Jatin M. Vyas ◽

Stuart M. Levitz

Keyword(s):

T Cells ◽

Dendritic Cells ◽

T Cell Activation ◽

Cell Activation ◽

Ex Vivo ◽

Interleukin 2 ◽

Mouse Lung

ABSTRACT Dendritic cells (DC) have been shown to phagocytose and kill Cryptococcus neoformans in vitro and are believed to be important for inducing protective immunity against this organism. Exposure to C. neoformans occurs mainly by inhalation, and in this study we examined the in vivo interactions of C. neoformans with DC in the lung. Fluorescently labeled live C. neoformans and heat-killed C. neoformans were administered intranasally to C57BL/6 mice. At specific times postinoculation, mice were sacrificed, and lungs were removed. Single-cell suspensions of lung cells were prepared, stained, and analyzed by microscopy and flow cytometry. Within 2 h postinoculation, fluorescently labeled C. neoformans had been internalized by DC, macrophages, and neutrophils in the mouse lung. Additionally, lung DC from mice infected for 7 days showed increased expression of the maturation markers CD80, CD86, and major histocompatibility complex class II. Finally, ex vivo incubation of lung DC from infected mice with Cryptococcus-specific T cells resulted in increased interleukin-2 production compared to the production by DC from naïve mice, suggesting that there was antigen-specific T-cell activation. This study demonstrated that DC in the lung are capable of phagocytosing Cryptococcus in vivo and presenting antigen to C. neoformans-specific T cells ex vivo, suggesting that these cells have roles in innate and adaptive pulmonary defenses against cryptococcosis.

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IL-12p40-overexpressing immature dendritic cells induce T cell hyporesponsiveness in vitro but accelerate allograft rejection in vivo: role of NK cell activation and interferon-gamma production

Immunology Letters ◽

10.1016/j.imlet.2004.05.001 ◽

2004 ◽

Vol 94 (3) ◽

pp. 191-199 ◽

Cited By ~ 9

Author(s):

Wenji Sun ◽

Xiaobo He ◽

Zhenhong Guo ◽

Quanxing Wang ◽

Xiaokang Li ◽

...

Keyword(s):

Dendritic Cells ◽

T Cell ◽

Interferon Gamma ◽

Allograft Rejection ◽

Cell Activation ◽

Nk Cell ◽

Immature Dendritic Cells

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The P2Y6 Receptor Stimulates Bone Resorption by Osteoclasts

Endocrinology ◽

10.1210/en.2011-1073 ◽

2011 ◽

Vol 152 (10) ◽

pp. 3706-3716 ◽

Cited By ~ 22

Author(s):

Isabel R. Orriss ◽

Ning Wang ◽

Geoffrey Burnstock ◽

Timothy R. Arnett ◽

Alison Gartland ◽

...

Keyword(s):

Cell Function ◽

Bone Cell ◽

Extracellular Nucleotides ◽

P2y6 Receptor ◽

Tomographic Analysis ◽

G Protein Coupled ◽

Resorptive Activity

Accumulating evidence indicates that extracellular nucleotides, signaling through P2 receptors, play a significant role in bone remodeling. Osteoclasts (the bone-resorbing cell) and osteoblasts (the bone-forming cell) display expression of the G protein-coupled P2Y6 receptor, but the role of this receptor in modulating cell function is unclear. Here, we demonstrate that extracellular UDP, acting via P2Y6 receptors, stimulates the formation of osteoclasts from precursor cells, while also enhancing the resorptive activity of mature osteoclasts. Furthermore, osteoclasts derived from P2Y6 receptor-deficient (P2Y6R−/−) animals displayed defective function in vitro. Using dual energy x-ray absorptiometry scanning and microcomputed tomographic analysis we showed that P2Y6R−/− mice have increased bone mineral content, cortical bone volume, and cortical thickness in the long bones and spine, whereas trabecular bone parameters were unaffected. Histomorphometric analysis showed the perimeter of the bone occupied by osteoclasts on the endocortical and trabecular surfaces was decreased in P2Y6R−/− mice. Taken together these results show the P2Y6 receptor may play an important role in the regulation of bone cell function in vivo.

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Dendritic cell-derived IL-2 production is regulated by IL-15 in humans and in mice

Blood ◽

10.1182/blood-2004-03-1059 ◽

2005 ◽

Vol 105 (2) ◽

pp. 697-702 ◽

Cited By ~ 65

Author(s):

Sonia Feau ◽

Valeria Facchinetti ◽

Francesca Granucci ◽

Stefania Citterio ◽

David Jarrossay ◽

...

Keyword(s):

Dendritic Cells ◽

T Cell ◽

Molecular Mechanisms ◽

Interleukin 2 ◽

Adaptive Immune ◽

Deficient Mice ◽

Mouse System

Abstract Dendritic cells (DCs) are involved in the initiation and regulation of innate and adaptive immune responses. Several molecular mechanisms regulate these diverse DC functions, and we have previously reported that mouse dendritic cells (mDCs) can produce interleukin-2 (IL-2) in vitro and in vivo, in response to microbial activation and T-cell-mediated stimuli. This property is shared by different DC subtypes, including Langerhans cells. Here we show that, on appropriate stimulation, human DCs, both plasmacytoid and myeloid subtypes, also express IL-2. Interestingly, the production of IL-2 by myeloid DCs is induced by T-cell-mediated stimuli and depends on the presence of IL-15. The key role of this cytokine in regulating IL-2 production was also confirmed in the mouse system. In particular, we could show that DCs from IL-15-deficient mice were strongly impaired in the ability to produce IL-2 after interactions with different microbial stimuli. Our results indicate that DC-produced IL-2 is tightly coregulated with the expression of IL-15.

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Role of LPXRFamide peptide in the neuroendocrine regulation of reproduction in fish

Open Life Sciences ◽

10.2478/s11535-011-0048-2 ◽

2011 ◽

Vol 6 (5) ◽

pp. 853-860 ◽

Cited By ~ 1

Author(s):

Md. Shahjahan ◽

Hironori Ando

Keyword(s):

Gonadal Development ◽

Gonadotropin Releasing Hormone ◽

Fish Reproduction ◽

Lower Vertebrates ◽

Hypothalamic Control ◽

G Protein Coupled ◽

Made In

AbstractThe decapeptide gonadotropin-releasing hormone (GnRH) is the primary factor responsible for the hypothalamic control of gonadotropin (GTH) secretion. This review focuses on a family of neuropeptides, LPXRFamide (LPXRFa) peptides, which have been implicated in the regulation of GTH secretion. LPXRFa acts on the pituitary via a G protein-coupled receptor, LPXRFa-R, to enhance gonadal development and maintenance by increasing gonadotropin release and synthesis. Because LPXRFa exists and functions in several fish species, LPXRFa is considered to be a key neurohormone in fish reproduction control. The precursors to LPXRFamide peptides encoded plural LPXRFamide peptides and were highly divergent in vertebrates, particularly in lower vertebrates. Tissue distribution analyses indicated that LPXRFamide peptides were highly concentrated in the hypothalamus and other brainstem regions. In view of the localization and expression of LPXRFamide peptides in the hypothalamo-hypophysial system, LPXRFamide peptide in fish increase GTH release in vitro and in vivo. This review summarizes the advances made in our understanding of the biosynthesis, mode of action and functional significance of LPXRFa, a newly discovered key neurohormone.

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Towards in vivo imaging of functionally active 5-HT1A receptors in schizophrenia: concepts and challenges

Translational Psychiatry ◽

10.1038/s41398-020-01119-3 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Oriane Razakarivony ◽

Adrian Newman-Tancredi ◽

Luc Zimmer

Keyword(s):

Psychiatric Disorders ◽

Cognitive Processes ◽

G Protein Coupled Receptors ◽

Research Paradigms ◽

New Research ◽

New Generation ◽

G Protein Coupled

AbstractThe serotonin 5-HT1A receptor has attracted wide attention as a target for treatment of psychiatric disorders. Although this receptor is important in the pharmacological mechanisms of action of new-generation antipsychotics, its characterization remains incomplete. Studies based on in vitro molecular imaging on brain tissue by autoradiography, and more recently in vivo PET imaging, have not yielded clear results, in particular due to the limitations of current 5-HT1A radiotracers, which lack specificity and/or bind to all 5-HT1A receptors, regardless of their functional status. The new concept of PET neuroimaging of functionally active G-protein-coupled receptors makes it possible to revisit PET brain exploration by enabling new research paradigms. For the 5-HT1A receptor it is now possible to use [18F]-F13640, a 5-HT1A receptor radioligand with high efficacy agonist properties, to specifically visualize and quantify functionally active receptors, and to relate this information to subjects’ pathophysiological or pharmacological state. We therefore propose imaging protocols to follow changes in the pattern of functional 5-HT1A receptors in relation to mood deficits or cognitive processes. This could allow improved discrimination of different schizophrenia phenotypes and greater understanding of the basis of therapeutic responses to antipsychotic drugs. Finally, as well as targeting functionally active receptors to gain insights into the role of 5-HT1A receptors, the concept can also be extended to the study of other receptors involved in the pathophysiology or therapy of psychiatric disorders.

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