Vitamins are essential constituents of our diet that have long been known to influence the immune system. Vitamins A and D have received particular attention in recent years as these vitamins have been shown to have an unexpected and crucial effect on the immune response. We present and discuss our current understanding of the essential roles of vitamins in modulating a broad range of immune processes, such as lymphocyte activation and proliferation, T-helper-cell differentiation, tissue-specific lymphocyte homing, the production of specific antibody isotypes and regulation of the immune response. Finally, we discuss the clinical potential of vitamin A and D metabolites for modulating tissue-specific immune responses and for preventing and/or treating inflammation and autoimmunity.

/pdf/vitamin-effects-on-the-immune-system-vitamins-a-and-d-take-2cygdunlqf.pdf

Vitamin effects on the immune system: vitamins A and D take centre stage

The term retinoid includes both natural and synthetic derivatives of vitamin A. Retinoid-containing treatments have been used since ~1550BC by the early Egyptians. Treatment of ichthyosiform disorders with retinoids dates back at least to the 1930s. Early use of high-dose vitamin A demonstrated efficacy, but because vitamin A is stored in the liver, toxicity limited usefulness. Interest turned to synthetic retinoids in an effort to enhance efficacy and limit toxicity. Acetretin, isotretinoin and, in the past etretinate, have provided the most effective therapy for ichthyosiform conditions. They have been used for a variety of ages, including in newborns with severe ichthyosis and for decades in some patients. Careful surveillance and management of mucous membrane, laboratory, skeletal, and teratogenic side effects has made systemic retinoids the mainstay of therapy for ichthyosis and related skin types.

/pdf/systemic-retinoids-in-the-management-of-ichthyoses-and-2t45j1ko6o.pdf

Systemic retinoids in the management of ichthyoses and related skin types

We have recently demonstrated that all-trans-retinoic acid (ATRA) and 9-cis-retinoic acid (9-cis RA) promote IL-4, IL-5 and IL-13 synthesis, while decreasing IFN-γ and TNF-α expression by activated human T cells and reduces the synthesis of IL-12p70 from accessory cells. Here, we have demonstrated that the observed effects using ATRA and 9-cis RA are shared with the clinically useful RAR ligand, 13-cis retinoic acid (13-cis RA), and the retinoic acid receptor-α (RAR-α)-selective agonist, AM580 but not with the RAR-β/γ ligand, 4-hydroxyphenylretinamide (4-HPR). The increase in type 2 cytokine production by these retinoids correlated with the expression of the T cell activation markers, CD69 and CD38. The RAR-α-selective agonist, AM580 recapitulated all of the T cell activation and type 2 cytokine-inducing effects of ATRA and 9-cis-RA, while the RAR-α-selective antagonist, RO 41–5253, inhibited these effects. These results strongly support a role for RAR-α engagement in the regulation of genes and proteins involved with human T cell activation and type 2 cytokine production.

/pdf/the-retinoic-acid-receptor-a-mediates-human-t-cell-3c7n16bko7.pdf

The Retinoic Acid Receptor-α mediates human T-cell activation and Th2 cytokine and chemokine production

Retinoic acid receptors, which act as heterodimers between either one of three RARs (RARa, b, g) and RXRs (RXRa, b, g), are exciting pharmacological targets for cancer and metabolic disease therapies. Studies of the action of retinoic acid on acute promyelocytic leukemia have converted one of the worst leukemias to one that has a most favorable prognosis and might possibly be fully curable following recent advances in the field. In addition, rexinoids are clinically used for the treatment of refractory T-cell leukemia, and novel treatment paradigms based on single-agent or combinatorial treatment are continuously being developed to exploit the enormous ACHTUNGTRENNUNGcytodifferentiation and apoptogenic potential of retinoids and rexinoids. The medicinal-chemistry approaches taken in this context are attempts to increase ligand potency, functionality (agonist, mixed agonist/antagonist, neutral antagonist, or inverse agonist), and receptor selectivity. In search of highly potent and receptor-selective retinoids, a series of silicon-containing RARand RXR-selective retinoid agonists has been synthesized and pharmacologically characterized in recent years. As part of this research project, we have been interested in the biological properties of the silicon analogues of the RARa-selective retinoid agonists AM80 (tamibaACHTUNGTRENNUNGrotene, 1 a) and AM580 (Ro-40-6055, 2 a), h, j, 6] disila-AM80 (disila-tamibarotene, 1 b) and disila-AM580 (2 b), respectively. In a series of earlier studies, the carbon/silicon switch (sila-substitution) strategy has been demonstrated to be a powerful tool for optimizing the pharmacodynamic and/or pharmacokinetic properties of drugs (for recent reviews on silicon-based drugs, see ref. [7]). In this context, disila-substitution of 1 a (!1 b) and 2 a (!2 b) was also very promising. Here we report on the synthesis of the silicon compounds 1 b and 2 b and the pharmacological characterization of the C/Si pairs 1 a/1 b and 2 a/ 2 b. These studies were performed as part of our systematic ACHTUNGTRENNUNGinvestigations on silicon-based drugs (for recent publications, see ref. [8]). Retinoids and rexinoids, as all other ligands of the nuclear receptor (NR) family, act as ligand-regulated trans-acting transcription factors that bind to cis-acting DNA regulatory elements in the promoter regions of target genes. Conceptually, ligand binding does nothing more than modulate the communication functions of the receptor with the intracellular environment, which entails essentially receptor–protein and receptor–DNA or receptor–chromatin interactions. In this communication network, the receptor serves at the same time as intracellular sensor and regulator of cell/organ functions. Receptors are mediators of the information encoded in the chemical structure of a nuclear receptor ligand, as they interpret this ACHTUNGTRENNUNGinformation in the context of cellular identity and cell physiological status and convert it into a dynamic chain of receptor– protein and receptor–DNA interactions. This interpretation is achieved by the allosteric effects that are exerted by a given (natural or synthetic) ligand on the cognate receptor, which result in two distinct events. The first event is the destabilization of the binding interface between the receptor and the corepressor complex (a complex that comprises among others epigenetically acting transcription-silencing histone deacetylases (HDACs)), which pre-exists on some promoters in the absence of ligands. Interestingly, some inverse agonists stabilize corepressor binding and thus act as superantagonists. 12] The second event is induced by the binding of an agonist to the [a] Prof. Dr. R. Tacke, V. M ller, Dr. M. W. B ttner, W. P. Lippert, Dr. R. Bertermann, Dr. J. O. Daiß Universit t W rzburg, Institut f r Anorganische Chemie Am Hubland, 97074 W rzburg (Germany) Fax: (+ 49) 931-888-4609 E-mail : r.tacke@uni-wuerzburg.de [b] H. Khanwalkar, A. Furst, Dr. C. Gaudon, Dr. H. Gronemeyer Department of Cancer Biology Institut de G n tique et de Biologie Mol culaire et Cellulaire (IGBMC) CNRS/INSERM/ULP B. P. 10142, 67404 Illkirch Cedex, C. U. de Strasbourg (France) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cmdc.200900257: NMR data and elemental analyses for compounds 1 b, 2 b, 5–10, 12, and 14.

Synthesis and Pharmacological Characterization of Disila-AM80 (Disila-tamibarotene) and Disila-AM580, Silicon Analogues of the RARα-Selective Retinoid Agonists AM80 (Tamibarotene) and AM580

Retinol-binding protein-4 (RBP4) and high-sensitivity C-reactive protein (hs-CRP) levels are associated with inflammation in patients with migraine. The release of proinflammatory cytokines during migraine results in recurrent sterile neurogenic inflammation. This study aimed to determine the correlation between RBP4 and hs-CRP levels, and migraine, which is considered an inflammatory disease. The study included 48 migraine patients and 40 age- and gender-matched controls. Migraine was diagnosed according to International Classification of Headache Disorders-II. The serum RBP4 level was measured using a commercial ELISA kit and hs-CRP was measured using an enzyme immunoassay test kit. The serum RBP4 level was significantly lower in the migraine patients than in the controls (P 0.05). Migraine headache severity, frequency and duration were not correlated with serum RBP or hs-CRP levels (P > 0.05). The observed high hs-CRP level and low RBP4 level in migraine patients suggest that vitamin A might play a major role in the pathogenesis of migraine. It is known that inflammation is a key factor in many diseases. Additional research might result in a better understanding of the anti-inflammatory effects of vitamin A.

Retinol-binding protein-4 and hs-CRP levels in patients with migraine

Retinoids have many pharmacological activities, including anti-inflammatory action and antiangiogenesis, effected through the regulation of various gene transcriptions. In this study, we investigated the effect of Am-80, one of the retinoic acid derivatives, on hapten-induced contact hypersensitivity in BALB/c mice. After application of 2,4-dinitrofluorobenzene (DNFB) to the ears of the mice, severe contact hypersensitivity with marked infiltration of inflammatory cells and hypertrophy of the epidermis was caused. The thickness of the ears increased biphasically and reached a peak 3 and 24 h after the DNFB challenge. Am-80 significantly inhibited ear thickness in the late-(24 h), but not the early-phase (3 h) reaction in a dose-dependent manner. In a histopathological study, obvious depression of edema and infiltration of inflammatory cells was observed in the ears of mice treated with Am-80. Am-80 inhibited the levels of expression in mice ears of interferon-γ (IFN-γ) and interleukin-6 (IL-6), but not tumor necrosis factor-α (TNF-α) or interleukin-4 (IL-4). Furthermore, Am-80 inhibited the antigen-induced production of some cytokines, including IFN-γ and IL-6, but not IL-4, in vitro. Therefore, Am-80 inhibited hapten-induced contact hypersensitivity through the direct inhibition of inflammatory cytokines such as IFN-γ and IL-6.

Effect of Am-80,a Retinoid Derivative, on 2,4-Dinitrofluorobenzene-induced Contact Dermatitis in Mice.

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Effect of Am-80,a Retinoid Derivative, on 2,4-Dinitrofluorobenzene-induced Contact Dermatitis in Mice.