tretinoin and Hypersensitivity

Vitamin A and vitamin D metabolites are ligands to nuclear receptors - namely RAR, RXR and VDR. The activation of these receptors in human B cells impacts B cell maturation and function. In this review, we discuss how 9-cis retinoic acid (9cRA) and 1,25-dihydroxyvitamin D3 (calcitriol) individually or in conjunction, signal through their nuclear receptors and thereby impact B cell differentiation, immunoglobulin class switching to IgA at the expense of IgE, and also B cell migration and homing. Impact of the vitamin metabolites individually on B cell survival factors are well elucidated, be it the regulation of BAFF and APRIL, the induction of TGF-β or suppression of NF-κB. Very little is known about the impact of 9cRA and calcitriol together on B cells. Recently our group revealed that 9cRA and calcitriol together in the context of the B cell differentiation, induces naïve B cell differentiation into IgA

Topics: Calcitriol; Cell Differentiation; Humans; Hypersensitivity; Immunoglobulin A; Immunoglobulin E; Receptors, Calcitriol; Receptors, Cytoplasmic and Nuclear; Retinoid X Receptors; Tretinoin; Vitamin A; Vitamin D; Vitamins

The mammalian gastrointestinal tract accommodates trillions of bacteria, many of which provide beneficial effects to the host, including protection from pathogenic microorganisms and essential metabolites. However, the intestinal immune system needs to adapt to the constantly fluctuating microbial environment at mucosal surfaces in order to maintain homeostasis. In particular, the gut microbiota induces the differentiation of effector Th17 cells and regulatory T cells (Tregs) that express RORγt, the master regulator of antimicrobial type 3 immunity. RORγt

Topics: Animals; Gastrointestinal Microbiome; Homeostasis; Humans; Hypersensitivity; Intestinal Mucosa; Intestines; Mice; Nuclear Receptor Subfamily 1, Group F, Member 3; Symbiosis; T-Lymphocytes, Regulatory; Th17 Cells; Tretinoin

 Vitamin A (VA) plays critical roles in gut homeostasis. Dendritic cells in mesenteric lymph nodes (MLN-DCs) can metabolize VA to retinoic acid (RA), thereby inducing gut-tropic lymphocytes and enhancing peripheral differentiation of regulatory T cells expressing forkhead box P3. We found that MLN-DCs from VA-deficient mice induced a distinct inflammatory T helper type 2 (Th2)-cell subset that produced abundant interleukin-13 (IL-13) and expressed receptors for homing to skin and inflammatory sites but not to the intestine. IL-6-neutralizing antibodies or RA abrogated the induction of this subset. On the other hand, RA receptor antagonists allowed MLN-DCs from VA-sufficient mice to induce a similar T-cell subset. IL-6 induced the differentiation of this subset from naive CD4

Topics: Animals; CD4-Positive T-Lymphocytes; Dendritic Cells; Hypersensitivity; Immunoglobulin E; Immunoglobulin G; Inflammation; Interleukin-13; Interleukin-6; Lymph Nodes; Mesentery; Mice; Th2 Cells; Tretinoin

Peanut is a potent inducer of proallergenic T. We sought to detect peanut protein (PN)-induced changes in gene expression in human myeloid dendritic cells (mDCs) and monocytes, identify signaling receptors that mediate these changes, and assess how PN-induced genes in mDCs impact their ability to promote T-cell differentiation.. mDCs, monocytes, and naive CD4. PN induced a unique gene expression profile in mDCs, including the gene that encodes retinaldehyde dehydrogenase 2 (RALDH2), a rate-limiting enzyme in the retinoic acid (RA)-producing pathway. Stimulation of mDCs with PN also induced a 7-fold increase in the enzymatic activity of RALDH2. Blocking antibodies against Toll-like receptor (TLR)1/TLR2, as well as small interfering RNA targeting TLR1/TLR2, reduced the expression of RALDH2 in PN-stimulated APCs by 70%. Naive T. PN induces RALDH2 in human APCs by signaling through the TLR1/TLR2 heterodimer. This leads to production of RA, which acts on T

Topics: Aldehyde Dehydrogenase 1 Family; Antigen-Presenting Cells; Arachis; CD4-Positive T-Lymphocytes; Cell Differentiation; Cells, Cultured; Dendritic Cells; HEK293 Cells; Humans; Hypersensitivity; Lymphocyte Activation; Monocytes; Retinal Dehydrogenase; Th2 Cells; Tretinoin

CD4

Topics: Animals; Epigenetic Repression; HEK293 Cells; Humans; Hypersensitivity; Interleukin-9; Lung; Mice; Mice, Inbred C57BL; Mice, Knockout; Pneumonia; Retinoic Acid Receptor alpha; Signal Transduction; T-Lymphocytes, Helper-Inducer; Transcription, Genetic; Tretinoin

Functional studies suggest that promoter polymorphisms of the Prostaglandin D Receptor (PTGDR) gene can be involved in asthma. All-trans Retinoic acid (ATRA) has also been linked to allergic diseases. We have previously described the PTGDR promoter activation mediated by ATRA through response elements (RARE) at position -549T> C. In this study we aimed to analyze the effect of retinoic acid (RA) on the expression of PTGDR, the production of cytokines as well as to evaluate the binding of RA receptors to RA-Response Elements (RARE) sequences. A549 cells were transfected with vectors carrying different PTGDR haplotypes and treated with all-Trans Retinoic Acid (ATRA). PTGDR expression was measured by qPCR. Chromatin Immunoprecipitation assays (ChIP) were performed in ATRA stimulated KU812 cells and in PBMCs of patients carrying CTCT, CCCC or CCCT haplotypes. In addition, a broad panel of cytokines was analyzed by cytometric bead assay in A549 cells. The expression of PTGDR increased in A549 cells transfected with PTGDR-variants. The CCCC haplotype showed a significantly higher expression compared with CTCT. However, we found that RA up-regulated PTGDR expression through RARα mainly in the CTCT variant. Experiments on PBMCs from allergic patients carrying the -549T and -549C variant of the PTGDR promoter after ATRA and RAR antagonist administration confirmed the modulation of PTGDR by ATRA. The cytokine analysis showed that IL4 and IL6 levels were significantly increased in A549 cells transfected with PTGDR. In addition, ATRA treatment decreased the levels of IL4, IL6 and TNFα in A549 cells, whereas it increased IL4 and TNFα levels in PTGDR-transfected cells. We observed genetic differences in the regulation of PTGDR by ATRA that could contribute to the phenotypic differences observed in allergic patients. Our findings showed that RAR modulation by PTGDR might have an impact on Th2 responses, suggesting that RAR could be a potential therapeutic target in allergic inflammation.

Topics: A549 Cells; Antineoplastic Agents; Cytokines; Female; Gene Expression Regulation; Humans; Hypersensitivity; Male; Mutation; Promoter Regions, Genetic; Receptors, Immunologic; Receptors, Prostaglandin; Receptors, Retinoic Acid; Response Elements; Signal Transduction; Transcriptional Activation; Tretinoin

The Vitamin-A-metabolite retinoic acid (RA) acts as a master regulator of cellular programs. Mast cells (MCs) are primary effector cells of type-I-allergic reactions. We recently uncovered that human cutaneous MCs are enriched with RA network components over other skin cells. Yet, direct experimental evidence on the significance of the RA-MC axis is limited. Here, skin-derived cultured MCs were exposed to RA for seven days and investigated by flow-cytometry (BrdU incorporation, Annexin/PI, FcεRI), microscopy, RT-qPCR, histamine quantitation, protease activity, and degranulation assays. We found that while MC size and granularity remained unchanged, RA potently interfered with MC proliferation. Conversely, a modest survival-promoting effect from RA was noted. The granule constituents, histamine and tryptase, remained unaffected, while RA had a striking impact on MC chymase, whose expression dropped by gene and by peptidase activity. The newly uncovered

Topics: Cell Cycle; Cell Degranulation; Cell Proliferation; Cell Survival; Cytoplasmic Granules; Histamine; Humans; Hypersensitivity; Immunoglobulin E; Mast Cells; Quantitative Trait, Heritable; Receptors, IgE; Skin; Tretinoin; Tryptases

Natural or synthetic agents can modify the immune system and, in some cases, impart a therapeutic benefit. Cancer, a disease of uncontrolled growth and spread of abnormal cells, is a major cause of death. The Vitamin A metabolite all-trans retinoic acid (ATRA) and its other active derivatives are potent modulators of cell growth and differentiation, and because it has an influence on cancer, it can be used as a chemotherapeutic and -preventive agent. To evaluate the immunomodulatory activity of ATRA, the impact of treatment on various parameters, e.g. delayed-type hypersensitivity (DTH), bone marrow cellularity, hematology, and levels of esterase-positive cells, was assessed in Balb/c mice. To evaluate antitumor effects of ATRA, tumor volume and host survival rate were monitored in B16F10 melanoma cell-injected mice. The results showed that administration of ATRA (0.60 mg/kg/dose, IP) caused a decrease in DTH (footpad thickness) in response to challenge with sheep red blood cells (SRBC) in SRBC-sensitized hosts. ATRA also caused increases in WBC counts and bone marrow cell numbers. In tumor-inoculated mice, ATRA caused tumor growth suppression and gave rise to a heightened survival rate. It was also found that ATRA had differential effects on serum levels of reduced glutathione (GSH) and nitric oxide (NO) was reduced in serum. Based on these results, we conclude that ATRA has a potent immunomodulatory potential but also could significantly impact upon solid tumor growth and prolong host survival.

Topics: Animals; Antineoplastic Agents; Bone Marrow Cells; Cell Line, Tumor; Erythrocytes; Glutathione; Hypersensitivity; Immunologic Factors; Male; Melanoma, Experimental; Mice; Mice, Inbred BALB C; Nitric Oxide; Sheep; Survival Rate; Tretinoin

Whereas thymic education eliminates most self-reactive T cells, additional mechanisms to promote tolerance in the periphery are critical to prevent excessive immune responses against benign environmental Ags and some self-Ags. In this study we show that murine CD4(+) recent thymic emigrants (RTEs) are programmed to facilitate tolerance in the periphery. Both in vitro and in vivo, naive RTEs more readily upregulate Foxp3 than do mature naive cells after stimulation under tolerogenic conditions. In RTEs, a relatively high sensitivity to retinoic acid contributes to decreased IFN-γ production, permitting the expression of Foxp3. Conversely, mature naive CD4 cells have a lower sensitivity to retinoic acid, resulting in increased IFN-γ production and subsequent IFN-γ-mediated silencing of Foxp3 expression. Enhanced retinoic acid signaling and Foxp3 induction in RTEs upon Ag encounter in the periphery may serve as form of secondary education that complements thymic education and helps avoid inappropriate immune responses. This mechanism for tolerance may be particularly important in settings where RTEs comprise a large fraction of the peripheral T cell pool, such as in newborns or after umbilical cord blood transplant.

Topics: Animals; Animals, Newborn; Autoantigens; Cell Movement; Forkhead Transcription Factors; Hypersensitivity; Immune Tolerance; Interferon-gamma; Lymph Nodes; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Spleen; Thymus Gland; Time Factors; Tretinoin

Retinoic acids (RAs), which are active metabolites of vitamin A, are known to enhance Th2-type immune responses in vitro, but the role of RAs in allergic inflammatory cells remains unclear. In this study, we demonstrated that purified peripheral blood eosinophils expressed nuclear receptors for RAs at the mRNA and protein levels. Eosinophils cultured with all-trans RA (ATRA) and 9-cis-RA showed dramatically induced cell survival and nuclear hypersegmentation, and the efficacy of RAs (10(-6)M) was similar to that of IL-5 (1 ng/ml), the most critical cytokine for eosinophil activation. Pharmacological manipulation with receptor-specific agonists and antagonists indicated that the antiapoptotic effect of RAs was mediated through ligand-dependent activation of both retinoid acid receptors and retinoid X receptors (mainly retinoid acid receptors). Furthermore, using a gene microarray and a cytokine Ab array, we discovered that RAs induced vascular endothelial growth factor, M-CSF, and MCP-1 secretion, although they were not involved in eosinophil survival. RA-induced eosinophil survival appears to be associated with down-regulation of caspase 3 and inhibition of its enzymatic activity. These findings indicate an important role of RAs in homeostasis of granulocytes and provide further insight into the cellular and molecular pathogenesis of allergic reactions.

Topics: Antineoplastic Agents; Apoptosis; Caspase 3; Cell Nucleus; Cell Survival; Chemokine CCL2; Down-Regulation; Endothelial Growth Factors; Eosinophils; Female; Gene Expression Regulation, Enzymologic; Homeostasis; Humans; Hypersensitivity; Inflammation; Interleukin-5; Macrophage Colony-Stimulating Factor; Male; Protein Array Analysis; Retinoid X Receptors; Th2 Cells; Tretinoin