Anhydroretinol: a naturally occurring inhibitor of lymphocyte physiology.

Buck, Jochen; Grün, Felix; Derguini, Fadila; Yq, Chen; Kimura, Shoji; Noy, Noa; Hämmerling, Ulrich

doi:10.1084/jem.178.2.675

Cited by 98 publications

(48 citation statements)

References 26 publications

(22 reference statements)

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“…These observations are in line with recent findings indicating that retinoids are important cofactors in murine T-cell activation and proliferation (7). Different vitamin A metabolites seemingly are physiological modulators, which control the proliferation and differentiation of lymphoid and myeloid cells (2,6). Thus, RA-induced HOXB gene induction may reflect a physiologic mechanism underlying T-cell activation.…”

supporting

confidence: 79%

Coordinate expression and proliferative role of HOXB genes in activated adult T lymphocytes.

Caré¹,

Testa²,

Bassani³

et al. 1994

Mol. Cell. Biol.

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We investigated the expression of HOXB cluster genes in purified phytohemagglutinin (PHA)-activated T lymphocytes from normal adult peripheral blood by reverse transcription PCR and RNase protection. These genes are not expressed in quiescent T cells, except for barely detectable Bi RNA. After the PHA stimulus, HOXB gene activation initiates coordinately as a rapid induction wave in the 3'->5' cluster direction (i.e., from HOXB1 through B9 genes). Thus, (i) expression of the foremost 3'-located Bi and B2 genes peaks 10 min after PHA addition and then rapidly declines, (ii) activation ofB3, B4, and B5 begins 10 min after PHA addition and peaks at later times (i.e., at 120 min for B5), (iii) B6, B7, and B9 are expressed at a low level starting at later times (45 to 60 min), and (iv) B8 remains silent. Treatment of PHA-activated T lymphocytes with antisense oligonucleotides to B2 or B4 mRNA causes a drastic inhibition of T-cell proliferation and a decreased expression of T-cell activation markers (i.e., interleukin 2 and transferrin receptors). Similarly, treatment of CEM-CCRF, Peer, and SEZ627 T acute lymphocytic leukemia cell lines with anti-B4 oligomer markedly inhibits cell proliferation. Finally, T cells stimulated by a low dosage of PHA in the presence of 1 tiM retinoic acid show a marked increase of both HOXB expression, particularly B2, and cell proliferation. These studies provide novel evidence on the role of HOX genes in adult cell proliferation. (i) Coordinate, early activation of HOXB genes from the 3'->5' cluster side apparently underlies T-cell activation. (ii) The expression pattern in adult PHA-activated T cells is strikingly similar to that observed in retinoic acid-induced teratocarcinoma cells

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supporting

confidence: 79%

Coordinate expression and proliferative role of HOXB genes in activated adult T lymphocytes.

Caré¹,

Testa²,

Bassani³

et al. 1994

Mol. Cell. Biol.

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“…They demonstrated that the retinol metabolite 14-hydroxy-4,14-retro-retinol (14-HRR) is responsible for the effects, and that anhydro-retinol reversed the effects of 14-HRR (Buck et al, 1991(Buck et al, , 1993. Similar effects have been observed in fibroblasts and promyelocytes: 14-HRR is a growth factor, whereas anhydro-retinol is an antagonist of the growth-promoting effect of 14-HRR.…”

Section: Mechanism Of Action Of Retro-retinoids Retinol and Other Rmentioning

confidence: 54%

Overview of retinoid metabolism and function

2006

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Retinoids (vitamin A) are crucial for most forms of life. In chordates, they have important roles in the developing nervous system and notochord and many other embryonic structures, as well as in maintenance of epithelial surfaces, immune competence, and reproduction. The ability of all-trans retinoic acid to regulate expression of several hundred genes through binding to nuclear transcription factors is believed to mediate most of these functions. The role of all-trans retinoic may extend beyond the regulation of gene transcription because a large number of noncoding RNAs also are regulated by retinoic acid. Additionally, extra-nuclear mechanisms of action of retinoids are also being identified. In organisms ranging from prokaryotes to humans, retinal is covalently linked to G protein-coupled transmembrane receptors called opsins. These receptors function as light-driven ion pumps, mediators of phototaxis, or photosensory pigments. In vertebrates phototransduction is initiated by a photochemical reaction where opsin-bound 11-cis-retinal is isomerized to all-trans-retinal. The photosensitive receptor is restored via the retinoid visual cycle. Multiple genes encoding components of this cycle have been identified and linked to many human retinal diseases. Central aspects of vitamin A absorption, enzymatic oxidation of all-trans retinol to all-trans retinal and all-trans retinoic acid, and esterification of all-trans retinol have been clarified. Furthermore, specific binding proteins are involved in several of these enzymatic processes as well as in delivery of all-trans retinoic acid to nuclear receptors. Thus, substantial progress has been made in our understanding of retinoid metabolism and function. This insight has improved our view of retinoids as critical molecules in vision, normal embryonic development, and in control of cellular growth, differentiation, and death throughout life.

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“…As previously reported, lymphocytes (normal T cells, transformed lymphoblastoid B cells, and T leukemia cells) undergo rapid PCD during nutritional vitamin A deprivation, when internal stores of retinyl-ester become depleted (6,16,47). Throughout our work AR is used as a tool to induce an acute state of vitamin A deficiency.…”

Section: Discussionmentioning

confidence: 87%

Vitamin A depletion causes oxidative stress, mitochondrial dysfunction, and PARP‐1‐dependent energy deprivation

2008

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A significant unresolved question is how vitamin A deprivation causes, and why retinoic acid fails to reverse, immunodeficiency. When depleted of vitamin A, T cells undergo programmed cell death (PCD), which is enhanced by the natural competitor of retinol, anhydroretinol. PCD does not happen by apoptosis, despite the occurrence of shared early events, including mitochondrial membrane depolarization, permeability transition pore opening, and cytochrome c release. It also lacks caspase-3 activation, chromatin condensation, and endonuclease-mediated DNA degradation, hallmarks of apoptosis. PCD following vitamin A deprivation exhibits increased production of reactive oxygen species (ROS), drastic reductions in ATP and NAD(+) levels, and activation of poly-(ADP-ribose) polymerase (PARP) -1. These latter steps are causative because neutralizing ROS, imposing hypoxic conditions, or inhibiting PARP-1 by genetic or pharmacologic approaches prevents energy depletion and PCD. The data highlight a novel regulatory role of vitamin A in mitochondrial energy homeostasis.

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Anhydroretinol: a naturally occurring inhibitor of lymphocyte physiology.

Cited by 98 publications

References 26 publications

Coordinate expression and proliferative role of HOXB genes in activated adult T lymphocytes.

Coordinate expression and proliferative role of HOXB genes in activated adult T lymphocytes.

Overview of retinoid metabolism and function

Vitamin A depletion causes oxidative stress, mitochondrial dysfunction, and PARP‐1‐dependent energy deprivation

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