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1.
J Allergy Clin Immunol ; 147(4): 1464-1477.e11, 2021 04.
Article in English | MEDLINE | ID: mdl-32920093

ABSTRACT

BACKGROUND: Autophagy plays an important role in causing inflammatory responses initiated by environmental pollutants and respiratory tract infection. OBJECTIVE: We sought to investigate the role of cockroach allergen-induced excessive activation of autophagy in allergic airway inflammation and its underlying molecular mechanisms. METHODS: Environmental allergen-induced autophagy was investigated in the primary human bronchial epithelial cells (HBECs) and lung tissues of asthmatic mouse model and patients. The role of autophagy in asthma development was examined by using autophagy inhibitor 3-methyladenine in an asthma mouse model. Furthermore, the involvements of reactive oxygen species (ROS) and oxidized Ca2+/calmodulin-dependent protein kinase II (ox-CaMKII) signaling in regulating autophagy during asthma were examined in allergen-treated HBECs and mouse model. RESULTS: Cockroach allergen activated autophagy in HBECs and in the lung tissues from asthmatic patients and mice. Autophagy inhibitor 3-methyladenine significantly attenuated airway hyperresponsiveness, TH2-associated lung inflammation, and ROS generation. Mechanistically, we demonstrated a pathological feedforward circuit between cockroach allergen-induced ROS and autophagy that is mediated through CaMKII oxidation. Furthermore, transgenic mice with ROS-resistant CaMKII MM-VVδ showed attenuation of TH2-associated lung inflammation and autophagy. Mitochondrial ox-CaMKII inhibition induced by adenovirus carrying mitochondrial-targeted inhibitor peptide CaMKIIN suppresses cockroach allergen-induced autophagy, mitochondrial dysfunction, mitophagy, and cytokine production in HBECs. Finally, mitochondrial CaMKII inhibition suppressed the expression of one of the key ubiquitin-binding autophagy receptors, optineurin, and its recruitment to fragmented mitochondria. Optineurin knockdown inhibited cockroach allergy-induced mitophagy. CONCLUSIONS: Our data suggest a previously uncovered axis of allergen-ROS-ox-CaMKII-mitophagy in the development of allergic airway inflammation and asthma.


Subject(s)
Allergens/immunology , Asthma/immunology , Calcium-Calmodulin-Dependent Protein Kinase Type 2/immunology , Cockroaches/immunology , Epithelial Cells/immunology , Mitophagy , Animals , Bronchi/cytology , Calcium-Calmodulin-Dependent Protein Kinase Type 2/genetics , Cells, Cultured , Cytokines/immunology , Female , Humans , Lung/immunology , Male , Mice, Inbred C57BL , Mice, Mutant Strains , Oxidation-Reduction , Reactive Oxygen Species/immunology
2.
Int Immunopharmacol ; 84: 106565, 2020 Jul.
Article in English | MEDLINE | ID: mdl-32388213

ABSTRACT

Natural or synthetic ligands for peroxisome proliferator-activated receptor gamma (PPAR-γ) represent an interesting tool for pharmacological interventions to treat inflammatory conditions. In particular, PPAR-γ activation prevents pain and inflammation in the temporomandibular joint (TMJ) by decreasing cytokine release and stimulating the synthesis of endogenous opioids. The goal of this study was to clarify whether PPAR-γ activation induces macrophage polarization, inhibiting inflammatory cytokine release and leukocyte recruitment. In addition, we investigated the involvement of heme oxygenase 1 (HO-1) in downstream events after PPAR-γ activation. Our results demonstrate that PPAR-γ activation ablates cytokine release by Bone Marrow-Derived Macrophages (BMDM) in vitro. 15d-PGJ2 induces the PPAR-γ heterodimer activation from rat macrophages, with macrophage polarization from M1-like cells toward M2-like cells. This response is mediated through HO-1. PPAR-γ activation diminished neutrophil migration induced by carrageenan, which was also HO-1 dependent. Ca2+/calmodulin expression did not change after PPAR-γ activation indicating that is not required for the activation of the intracellular L-arginine/NO/cGMP/K+ATP channel pathway. In summary, the anti-inflammatory actions induced by PPAR-γ activation involve macrophage polarization. HO-1 expression is increased and HO-1 activity is required for the suppression of neutrophil migration.


Subject(s)
Heme Oxygenase-1/immunology , Macrophages/immunology , Neutrophils/physiology , PPAR gamma/immunology , Anilides/pharmacology , Animals , Calcium-Calmodulin-Dependent Protein Kinase Type 2/immunology , Carrageenan/pharmacology , Cell Movement/drug effects , Cells, Cultured , Cytokines/immunology , Humans , Lipopolysaccharides/pharmacology , Macrophages/drug effects , Male , Mice, Inbred C57BL , Neutrophils/drug effects , Nitric Oxide/immunology , Prostaglandin D2/analogs & derivatives , Prostaglandin D2/pharmacology , Rats, Wistar , Temporomandibular Joint/drug effects , Temporomandibular Joint/immunology
3.
J Allergy Clin Immunol ; 141(2): 586-600.e6, 2018 02.
Article in English | MEDLINE | ID: mdl-28689792

ABSTRACT

BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is associated with mast cell-mediated inflammation and heightened oxidant stress. Kynurenine (KYN), an endogenous tryptophan metabolite, can promote allergen-induced mast cell activation through the aryl hydrocarbon receptor (AhR). OBJECTIVES: We sought to determine the role of the KYN/AhR axis and oxidant stress in mast cell activation and the development of CRSwNP. METHODS: We measured the expression of indoleamine 2,3-dioxygenase 1, tryptophan 2,3-dioxygenase, KYN, and oxidized calmodulin-dependent protein kinase II (ox-CaMKII) in nasal polyps and controls. KYN-potentiated ovalbumin (OVA)-induced ROS generation, cell activation, and ox-CaMKII expression were investigated in wild-type and AhR-deficient (AhR-/-) mast cells. The role of ox-CaMKII in mast cell activation was further investigated. RESULTS: Nasal polyps in CRSwNP showed an increased expression of indoleamine 2,3-dioxygenase 1, tryptophan2,3-dioxygenase, and KYN compared with controls. AhR was predominantly expressed in mast cells in nasal polyps. Activated mast cells and local IgE levels were substantially increased in eosinophilic polyps compared with noneosinophilic polyps and controls. Furthermore, KYN potentiated OVA-induced ROS generation, intracellular Ca2+ levels, cell activation, and expression of ox-CaMKII in wild-type, but not in AhR-/- mast cells. Compared with noneosinophilic polyps and controls, eosinophilic polyps showed increased expression of ox-CaMKII in mast cells. Mast cells from ROS-resistant CaMKII MMVVδ mice or pretreated with CaMKII inhibitor showed protection against KYN-promoted OVA-induced mast cell activation. CONCLUSIONS: These studies support a potentially critical but previously unidentified function of the KYN/AhR axis in regulating IgE-mediated mast cell activation through ROS and ox-CaMKII in CRSwNP.


Subject(s)
Basic Helix-Loop-Helix Transcription Factors/immunology , Nasal Polyps/immunology , Receptors, Aryl Hydrocarbon/immunology , Receptors, Glutamate/immunology , Rhinitis/immunology , Sinusitis/immunology , Animals , Basic Helix-Loop-Helix Transcription Factors/genetics , Calcium-Calmodulin-Dependent Protein Kinase Type 2/genetics , Calcium-Calmodulin-Dependent Protein Kinase Type 2/immunology , Chronic Disease , Eosinophils/immunology , Eosinophils/pathology , Humans , Indoleamine-Pyrrole 2,3,-Dioxygenase/genetics , Indoleamine-Pyrrole 2,3,-Dioxygenase/immunology , Mast Cells/immunology , Mast Cells/pathology , Mice , Mice, Knockout , Nasal Polyps/genetics , Nasal Polyps/pathology , Receptors, Aryl Hydrocarbon/genetics , Receptors, Glutamate/genetics , Rhinitis/genetics , Rhinitis/pathology , Signal Transduction/genetics , Signal Transduction/immunology , Sinusitis/genetics , Sinusitis/pathology
4.
Nat Commun ; 6: 6795, 2015 Apr 13.
Article in English | MEDLINE | ID: mdl-25865065

ABSTRACT

To date, the activities of protein kinases have formed the core of our understanding of cell signal transduction. Comprehension of the extent of protein acetylation has raised expectations that this alternate post-transcriptional modification will be shown to rival phosphorylation in its importance in mediating cellular responses. However, limited instances have been identified. Here we show that signalling from Toll-like or TNF-α receptors triggers the calcium/calmodulin-dependent protein kinase (CaMK2) to activate histone acetyltransferase-1 (HAT1), which then acetylates the transcriptional regulator PLZF. Acetylation of PLZF promotes the assembly of a repressor complex incorporating HDAC3 and the NF-κB p50 subunit that limits the NF-κB response. Accordingly, diminishing the activity of CaMK2, the expression levels of PLZF or HAT1, or mutating key residues that are covalently modified in PLZF and HAT1, curtails control of the production of inflammatory cytokines. These results identify a central role for acetylation in controlling the inflammatory NF-κB transcriptional programme.


Subject(s)
Histone Acetyltransferases/genetics , Kruppel-Like Transcription Factors/genetics , NF-kappa B/genetics , Protein Processing, Post-Translational , Transcription, Genetic , Acetylation , Animals , Calcium-Calmodulin-Dependent Protein Kinase Type 2/genetics , Calcium-Calmodulin-Dependent Protein Kinase Type 2/immunology , Histone Acetyltransferases/immunology , Histone Deacetylases/genetics , Histone Deacetylases/immunology , Immunity, Innate , Inflammation/chemically induced , Inflammation/genetics , Inflammation/immunology , Inflammation/pathology , Kruppel-Like Transcription Factors/deficiency , Kruppel-Like Transcription Factors/immunology , Lipopolysaccharides , Mice , Mice, Inbred C57BL , Mice, Knockout , Mutation , NF-kappa B/immunology , Promyelocytic Leukemia Zinc Finger Protein , Receptors, Tumor Necrosis Factor/genetics , Receptors, Tumor Necrosis Factor/immunology , Signal Transduction
5.
BMC Cell Biol ; 15: 24, 2014 Jun 30.
Article in English | MEDLINE | ID: mdl-24974801

ABSTRACT

BACKGROUND: Chronic inflammation-mediated ß-cell apoptosis is known to decrease ß-cell mass in diabetes leading to reduced insulin secretion. Exposure to pro-inflammatory cytokines can stimulate apoptosis in pancreatic ß-cells. The G protein coupled receptor 40 (GPR40) is implicated for glucose induced insulin secretion. We hypothesized that GPR40 activation can protect ß-cells from inflammation-induced apoptosis and restore glucose stimulated insulin secretion. RESULTS: By exposing NIT1 insulinoma cells and rat islets to a cocktail of pro-inflammatory cytokines (TNFα and IL1ß), we mimicked inflammatory signaling as seen by JNK and NFκB activation and increased mRNA levels of TNFα, IL1ß and NOS2a. These changes were reversed by pharmacological activation of GPR40 by a specific, small molecule, CNX-011-67. Further, GPR40 activation reduced inflammation-mediated oxidative and endoplasmic reticulum (ER) stresses. Importantly, GPR40 activation decreased inflammation-induced apoptosis as measured by key markers. These impacts of GPR40 were mediated through activation of PLC, CaMKII, calcineurin and cAMP. Cell survival was also enhanced by GPR40 activation as seen from the increased phosphorylation of Akt/PKB and enhanced expression of BCL2 and PDX1 genes. Interestingly, GPR40 activation restored both, inflammation-mediated inhibition on insulin secretion and intracellular insulin content. CONCLUSIONS: In this study, we provide evidences that CNX-011-67, a GPR40 agonist, reduces inflammatory signaling and apoptosis in pancreatic ß-cells while promoting insulin secretion and synthesis. Activation of GPR40 leads to attenuation of ß-cell dysfunction caused by chronic inflammation and thus could be of immense clinical value to improve insulin secretion and ß-cell survival.


Subject(s)
Anti-Inflammatory Agents/pharmacology , Inflammation/drug therapy , Insulin-Secreting Cells/drug effects , Insulin-Secreting Cells/immunology , Receptors, G-Protein-Coupled/agonists , Animals , Apoptosis/drug effects , Calcineurin/immunology , Calcium-Calmodulin-Dependent Protein Kinase Type 2/immunology , Cell Line , Cells, Cultured , Chronic Disease , Glucose/immunology , Inflammation/immunology , Insulin/immunology , Islets of Langerhans/drug effects , Islets of Langerhans/immunology , Male , Rats , Rats, Wistar , Receptors, G-Protein-Coupled/immunology , Signal Transduction/drug effects
6.
Eur J Immunol ; 44(5): 1285-98, 2014 May.
Article in English | MEDLINE | ID: mdl-24470136

ABSTRACT

Suppressory B-cell function controls immune responses and is mainly dependent on IL-10 secretion. Pharmacological manipulation of B-cell-specific IL-10 synthesis could, thus, be therapeutically useful in B-cell chronic lymphocytic leukemia, transplantation, autoimmunity and sepsis. TLR are thought to play a protagonistic role in the formation of IL-10-secreting B cells. The aim of the study was to identify the molecular events selectively driving IL-10 production in TLR9-stimulated human B cells. Our data highlight the selectivity of calcineurin inhibitors in blocking TLR9-induced B-cell-derived IL-10 transcription and secretion, while IL-6 transcription and release, B-cell proliferation, and differentiation remain unaffected. Nevertheless, TLR9-induced IL-10 production was found to be independent of calcineurin phosphatase activity and was even negatively regulated by NFAT. In contrast to TLR9-induced IL-6, IL-10 secretion was highly sensitive to targeting of spleen tyrosine kinase (syk) and Bruton's tyrosine kinase. Further analyses demonstrated increased phosphorylation of Ca(2+) /calmodulin kinase II (CaMKII) in TLR9-stimulated B cells and selective reduction of TLR9-induced secretion of IL-10 upon treatment with CaMKII inhibitors, with negligible impact on IL-6 levels. Altogether, our results identify calcineurin antagonists as selective inhibitors of IL-10 transcription and syk/Bruton´s tyrosine kinase-induced Ca(2+) /calmodulin- and CaMKII-dependent signaling as a pathway regulating the release of TLR9-induced B-cell-derived IL-10.


Subject(s)
B-Lymphocyte Subsets/immunology , Calcium Signaling/physiology , Interleukin-10/immunology , Toll-Like Receptor 9/immunology , Transcription, Genetic/physiology , Agammaglobulinaemia Tyrosine Kinase , B-Lymphocyte Subsets/cytology , Calcineurin/immunology , Calcineurin/metabolism , Calcineurin Inhibitors , Calcium-Calmodulin-Dependent Protein Kinase Type 2/antagonists & inhibitors , Calcium-Calmodulin-Dependent Protein Kinase Type 2/immunology , Calcium-Calmodulin-Dependent Protein Kinase Type 2/metabolism , Cell Proliferation , Enzyme Inhibitors/pharmacology , Female , Gene Expression Regulation/physiology , Humans , Interleukin-10/metabolism , Interleukin-6/biosynthesis , Interleukin-6/immunology , Intracellular Signaling Peptides and Proteins/immunology , Intracellular Signaling Peptides and Proteins/metabolism , Male , NFATC Transcription Factors/immunology , NFATC Transcription Factors/metabolism , Protein-Tyrosine Kinases/immunology , Protein-Tyrosine Kinases/metabolism , Syk Kinase
7.
Mol Cell Biol ; 34(1): 123-31, 2014 Jan.
Article in English | MEDLINE | ID: mdl-24190965

ABSTRACT

La antigen (Sjögren's syndrome antigen B) is a phosphoprotein associated with nascent precursor tRNAs and other RNAs, and it is targeted by autoantibodies in patients with Sjögren's syndrome, systemic lupus erythematosus, and neonatal lupus. Increased levels of La are associated with leukemias and other cancers, and various viruses usurp La to promote their replication. Yeast cells (Saccharomyces cerevisiae and Schizosaccharomyces pombe) genetically depleted of La grow and proliferate, whereas deletion from mice causes early embryonic lethality, raising the question of whether La is required by mammalian cells generally or only to surpass a developmental stage. We developed a conditional La allele and used it in mice that express Cre recombinase in either B cell progenitors or the forebrain. B cell Mb1(Cre) La-deleted mice produce no B cells. Consistent with αCamKII Cre, which induces deletion in hippocampal CA1 cells in the third postnatal week and later throughout the neocortex, brains develop normally in La-deleted mice until ∼5 weeks and then lose a large amount of forebrain cells and mass, with evidence of altered pre-tRNA processing. The data indicate that La is required not only in proliferating cells but also in nondividing postmitotic cells. Thus, La is essential in different cell types and required for normal development of various tissue types.


Subject(s)
Autoantigens/immunology , B-Lymphocytes/immunology , Frontal Lobe/immunology , Neurons/immunology , Ribonucleoproteins/immunology , Animals , Autoantigens/genetics , Autoantigens/metabolism , B-Lymphocytes/metabolism , Calcium-Calmodulin-Dependent Protein Kinase Type 2/genetics , Calcium-Calmodulin-Dependent Protein Kinase Type 2/immunology , Calcium-Calmodulin-Dependent Protein Kinase Type 2/metabolism , Cell Survival/genetics , Cell Survival/immunology , Frontal Lobe/metabolism , Frontal Lobe/pathology , Hippocampus/immunology , Hippocampus/metabolism , Hippocampus/pathology , Humans , Immunohistochemistry , Mice , Mice, Knockout , Mice, Transgenic , Neurons/metabolism , RNA/genetics , RNA/immunology , RNA/metabolism , RNA Precursors/genetics , RNA Precursors/immunology , RNA Precursors/metabolism , RNA, Transfer/genetics , RNA, Transfer/immunology , RNA, Transfer/metabolism , Ribonucleoproteins/genetics , Ribonucleoproteins/metabolism , Sjogren's Syndrome/genetics , Sjogren's Syndrome/immunology , Sjogren's Syndrome/metabolism , Time Factors , SS-B Antigen
8.
J Biol Chem ; 288(18): 12448-58, 2013 May 03.
Article in English | MEDLINE | ID: mdl-23515313

ABSTRACT

Pattern recognition receptors expressed by cells of the innate immune system initiate the immune response upon recognition of microbial products. Activation of pattern recognition receptors result in the production and release of proinflammatory cytokines, including TNFα and IL-6. Because these cytokines promote disparate effector cell responses, understanding the signaling pathways involved in their regulation is critical for directing the immune response. Using macrophages and dendritic cells deficient in spleen tyrosine kinase (Syk), we identified a novel pathway by which TNFα trafficking and secretion are regulated by Syk following stimulation with CpG DNA. In the absence of PLCγ2, a Syk substrate, or the calcium-responsive kinase calcium calmodulin kinase II, CpG-induced TNFα secretion was impaired. Forced calcium mobilization rescued the TNFα secretion defect in Syk-deficient cells. In contrast to its effect on TNFα, Syk deficiency did not affect IL-6 secretion, suggesting that Syk-dependent signals participate in differential sorting of cytokines, thus tailoring the cytokine response. Our data report a novel pathway for TNFα regulation and provide insight into non-transcriptional mechanisms for shaping cytokine responses.


Subject(s)
Adjuvants, Immunologic/pharmacology , Calcium Signaling/drug effects , Intracellular Signaling Peptides and Proteins/metabolism , Macrophages/metabolism , Oligodeoxyribonucleotides/pharmacology , Protein-Tyrosine Kinases/metabolism , Tumor Necrosis Factor-alpha/metabolism , Animals , Calcium Signaling/genetics , Calcium Signaling/immunology , Calcium-Calmodulin-Dependent Protein Kinase Type 2/genetics , Calcium-Calmodulin-Dependent Protein Kinase Type 2/immunology , Calcium-Calmodulin-Dependent Protein Kinase Type 2/metabolism , Cell Line , Exocytosis/drug effects , Exocytosis/genetics , Exocytosis/immunology , Immunity, Innate/drug effects , Immunity, Innate/genetics , Interleukin-6/genetics , Interleukin-6/immunology , Interleukin-6/metabolism , Intracellular Signaling Peptides and Proteins/genetics , Intracellular Signaling Peptides and Proteins/immunology , Macrophages/immunology , Mice , Mice, Transgenic , Phospholipase C gamma/genetics , Phospholipase C gamma/immunology , Phospholipase C gamma/metabolism , Protein-Tyrosine Kinases/genetics , Protein-Tyrosine Kinases/immunology , Syk Kinase , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/immunology
9.
J Immunol ; 185(12): 7244-51, 2010 Dec 15.
Article in English | MEDLINE | ID: mdl-21068402

ABSTRACT

MicroRNAs (miRNAs) are involved in the regulation of immunity, including the lymphocyte development and differentiation, and inflammatory cytokine production. Dendritic cells (DCs) play important roles in linking innate and adaptive immune responses. However, few miRNAs have been found to regulate the innate response and APC function of DCs to date. Calcium/calmodulin-dependent protein kinase II (CaMKII), a major downstream effector of calcium (Ca(2+)), has been shown to be an important regulator of the maturation and function of DCs. Our previous study showed that CaMKIIα could promote TLR-triggered production of proinflammatory cytokines and type I IFN. Inspired by the observations that dicer mutant Drosophila display defect in endogenous miRNA generation and higher CaMKII expression, we wondered whether miRNAs can regulate the innate response and APC function of DCs by targeting CaMKIIα. By predicting with software and confirming with functional experiments, we demonstrate that three members of the miRNA (miR)-148 family, miR-148a, miR-148b, and miR-152, are negative regulators of the innate response and Ag-presenting capacity of DCs. miR-148/152 expression was upregulated, whereas CaMKIIα expression was downregulated in DCs on maturation and activation induced by TLR3, TLR4, and TLR9 agonists. We showed that miR-148/152 in turn inhibited the production of cytokines including IL-12, IL-6, TNF-α, and IFN-ß upregulation of MHC class II expression and DC-initiated Ag-specific T cell proliferation by targeting CaMKIIα. Therefore, miRNA-148/152 can act as fine-tuner in regulating the innate response and Ag-presenting capacity of DCs, which may contribute to the immune homeostasis and immune regulation.


Subject(s)
Calcium-Calmodulin-Dependent Protein Kinase Type 2/immunology , Dendritic Cells/immunology , Gene Expression Regulation/immunology , Immunity, Innate/physiology , MicroRNAs/immunology , Animals , Calcium-Calmodulin-Dependent Protein Kinase Type 2/biosynthesis , Cytokines/immunology , Cytokines/metabolism , Dendritic Cells/cytology , Dendritic Cells/metabolism , Drosophila melanogaster , Mice , MicroRNAs/biosynthesis , Toll-Like Receptors/immunology , Toll-Like Receptors/metabolism
10.
J Biol Chem ; 284(12): 7578-87, 2009 Mar 20.
Article in English | MEDLINE | ID: mdl-19019824

ABSTRACT

Impaired cellular immunity caused by decreased production of Th1-type cytokines, including interleukin-12 (IL-12) is a major feature of HIV-1-associated immunodeficiency and acquired immunodeficiency syndrome. IL-12p40, an inducible subunit shared between IL-12 and IL-23, plays a critical role in the development of cellular immunity, and its production is significantly decreased during HIV infection. The mechanism by which HIV induces loss of IL-12p40 production remains poorly understood. We have previously shown that lipopolysaccharide (LPS)-induced IL-12p40 production in monocytic cells is regulated by NFkappaB and AP-1 transcription factors through the activation of two distinct upstream signaling pathways, namely the c-Jun-N-terminal kinase (JNK) and the calmodulin-dependent protein kinase-II-activated pathways. Herein, we show that intracellular nef expressed through transduction of primary monocytes and promonocytic THP-1 cells with retroviral-mediated nef gene inhibited LPS-induced IL-12p40 transcription by inhibiting the JNK mitogen-activated protein kinases without affecting the calmodulin-dependent protein kinase-II-activated pathway. In addition, nef inhibited JNK-activated NFkappaB without affecting the AP-1 activity. Overall, our results suggest for the first time that intracellular nef inhibited LPS-activated JNK, which may cause inhibition of IL-12p40 expression in human monocytic cells by selectively inhibiting NFkappaB activity.


Subject(s)
Acquired Immunodeficiency Syndrome/metabolism , Gene Expression Regulation , HIV-1/metabolism , Interleukin-12 Subunit p40/biosynthesis , Lipopolysaccharides/pharmacology , MAP Kinase Kinase 4/metabolism , Monocytes/metabolism , NF-kappa B/metabolism , nef Gene Products, Human Immunodeficiency Virus/metabolism , Animals , Calcium-Calmodulin-Dependent Protein Kinase Type 2/immunology , Calcium-Calmodulin-Dependent Protein Kinase Type 2/metabolism , HIV-1/immunology , Humans , Immunity, Cellular/drug effects , Interleukin-23/immunology , Interleukin-23/metabolism , MAP Kinase Kinase 4/immunology , Mice , Monocytes/immunology , NF-kappa B/immunology , NIH 3T3 Cells , Transcription Factor AP-1/immunology , Transcription Factor AP-1/metabolism , Transcription, Genetic/drug effects , nef Gene Products, Human Immunodeficiency Virus/immunology
11.
Immunol Res ; 39(1-3): 115-27, 2007.
Article in English | MEDLINE | ID: mdl-17917060

ABSTRACT

Dendritic cells (DC) are the sentinels of the immune system, linking innate with adaptive responses. The functional responses of DC are subject to complex regulation and serve as targets for pathogens. Ca2+-mediated signal transduction pathways serve a central regulatory role in DC responses to diverse antigens, including TLR ligands, intact bacteria, and microbial toxins. This review summarizes the major mechanisms of Ca2+-signaling that DC utilize to regulate maturation and antigen presentation, including a Ca2+-calmodulin (CaM)-CaM kinase II pathway that is localized to phagosomes and is targeted by the human intracellular pathogen, Mycobacterium tuberculosis. Restoration of functional Ca2+ signaling in DC may provide a novel mechanism to enhance therapy and promote vaccine efficacy to infectious diseases, including tuberculosis.


Subject(s)
Antigen Presentation , Calcium Signaling , Calcium-Calmodulin-Dependent Protein Kinase Type 2/metabolism , Dendritic Cells/immunology , Dendritic Cells/metabolism , Calcium-Calmodulin-Dependent Protein Kinase Type 2/immunology , Calmodulin/metabolism , Humans , Mycobacterium tuberculosis/immunology , Phagocytes/immunology , Phagocytes/metabolism , Phagosomes/immunology , Phagosomes/metabolism
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