Important note: Information in this article was accurate in 1996. The state of the art may have changed since the publication date.
Vitamin A down-regulation of IFN-gamma synthesis in cloned mouse Th1 lymphocytes depends on the CD28 costimulatory pathway.
J Immunol. 1996 Apr 15;156(8):2674-9. Unique Identifier : AIDSLINE MED/96183217 Cantorna MT; Nashold FE; Chun TY; Hayes CE; Department of Biochemistry, University of Wisconsin-Madison, WI; 53706, USA.
Abstract:
Some infections deplete serum retinol, low retinol reduces immunity, and reduced immunity establishes susceptibility to further infection in a cyclical relationship that is poorly understood. We showed that when retinol was low, there was excessive Th1 cell IFN-gamma synthesis and inadequate Th2 cell IL-4 and IL-5 synthesis. The retinol metabolite retinoic acid inhibited the IFN-gamma stimulatory activity of APCs, enhanced Th2 cell differentiation, and inhibited Th1 cell IFN-gamma synthesis. Here we focus on the mechanism for retinoic acid inhibition of IFN-gamma synthesis in myelin basic protein-specific MM4 Th1 cells. Physiologic amounts of all-trans-retinoic acid directly and specifically down-regulated the MM4 Th1 cell IFN-gamma secretion rate in vitro without affecting cell growth, viability, or overall protein synthesis. All-trans-, 9-cis-, and 13-cis-retinoic acid, and the synthetic retinoid Ch55, inhibited IFN-gamma synthesis effectively, whereas retinaldehyde, retinol, and retinyl acetate did not. This pattern suggests retinoic acid receptor involvement in the inhibition mechanism. Retinoic acid did not inhibit when Th1 cells were activated only through the TCR/CD3 complex, with or without IL-2 costimulation. Retinoic acid inhibited IFN-gamma synthesis when the CD28 costimulatory pathway was activated in addition to the TCR/CD3 pathway, suggesting it blocks some step in the CD28 pathway. Retinoid probably acted to decrease IFN-gamma transcript accumulation by decreasing transcription because it did not decrease transcript stability. We suggest that unrestrained IFN-gamma synthesis is one key immunobiologic mechanism that accounts for poor antibody-mediated immunity in hypovitaminosis A, since IFN-gamma in relatively small amounts can limit Th2 cell growth and interfere with the B cell stimulatory functions of Th2 cell cytokines.
Keywords: Animal Antigen-Presenting Cells/DRUG EFFECTS Antigens, CD28/DRUG EFFECTS/*PHYSIOLOGY Cloning, Molecular Down-Regulation (Physiology)/DRUG EFFECTS/*IMMUNOLOGY Interferon Type II/*BIOSYNTHESIS/*DRUG EFFECTS/GENETICS Interleukin-4/BIOSYNTHESIS Interleukin-5/BIOSYNTHESIS Mice Mice, Inbred Strains Signal Transduction/DRUG EFFECTS/*IMMUNOLOGY Support, Non-U.S. Gov't Support, U.S. Gov't, P.H.S. Th1 Cells/*DRUG EFFECTS/*METABOLISM Transcription, Genetic/DRUG EFFECTS Vitamin A/ANALOGS & DERIVATIVES/*PHARMACOLOGY JOURNAL ARTICLE 960830
M9681186
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Important note: Information in this article was accurate in 1996. The state of the art may have changed since the publication date.
