Elder J T, Aström A, Pettersson U, Tavakkol A, Griffiths C E, Krust A, Kastner P, Chambon P, Voorhees J J
Department of Dermatology, University of Michigan, Ann Arbor 48109-0672.
J Invest Dermatol. 1992 May;98(5):673-9. doi: 10.1111/1523-1747.ep12499896.
Many of the pleiotropic effects of retinoids are likely to be mediated by nuclear retinoic acid receptors (RAR) acting as ligand-dependent enhancer factors. However, in previous studies we have been unable to document altered RAR expression at the RNA level in response to retinoic acid (RA) treatment or in psoriatic lesions, conditions characterized by marked alterations in keratinocyte proliferation and differentiation, which are either caused by or responsive to RA. In an attempt to identify other potential regulators of RA responsiveness, we have used RNA blot hybridization to study the expression of the cellular retinoic acid binding proteins (CRABP) CRABP-I and CRABP-II, the RAR-gamma isoforms RAR-gamma 1 and RAR-gamma 2, and the low-affinity RAR homologue RXR in normal, RA-treated, and psoriatic human epidermis. CRABP-II is selectively and markedly induced by RA in adult human skin (J Biol Chem 266:17662-17666, 1991). However, in submerged, serum-free keratinocyte cultures, CRABP-II mRNA could not be induced by RA. Comparisons of intact human skin, submerged keratinocyte cultures, and human skin equivalent cultures indicated that induction of CRABP-II by RA requires epidermal stratification, dermal-epidermal interactions, or both. CRABP-II transcripts were also expressed in heat-separated human dermis at levels similar to those found in epidermal keratome biopsies, whereas CRABP-I transcripts were undetectable in dermal RNA. CRABP-II transcripts were markedly elevated in psoriatic lesions, as they were in RA-treated skin. In contrast, CRABP-I mRNA was undetectable and not increased in psoriatic lesions. Expression of RAR-gamma isoforms and RXR was not detectably altered in either psoriatic lesions or in RA-treated skin. Thus, altered expression of CRABP-II appears more likely to regulate the cutaneous actions of RA than does altered expression of CRABP-I, RXR, or RAR-gamma isoforms. From these and other results, a model for regulation of RA action involving sequestration of RA by CRABP-II is proposed.
类视黄醇的许多多效性作用可能是由作为配体依赖性增强因子的核视黄酸受体（RAR）介导的。然而，在先前的研究中，我们无法证明在视黄酸（RA）处理后或在银屑病皮损（其特征为角质形成细胞增殖和分化发生显著改变，这些改变要么由RA引起，要么对RA有反应）中，RAR在RNA水平上的表达有变化。为了确定RA反应性的其他潜在调节因子，我们使用RNA印迹杂交来研究细胞视黄酸结合蛋白（CRABP）CRABP-I和CRABP-II、RAR-γ亚型RAR-γ1和RAR-γ2以及低亲和力RAR同源物RXR在正常、RA处理的和银屑病患者的人表皮中的表达。CRABP-II在成人皮肤中被RA选择性且显著地诱导（《生物化学杂志》266:17662 - 17666, 1991）。然而，在浸没的无血清角质形成细胞培养物中，RA不能诱导CRABP-II mRNA。对完整人皮肤、浸没的角质形成细胞培养物和人皮肤等效物培养物的比较表明，RA诱导CRABP-II需要表皮分层、真皮-表皮相互作用或两者都需要。CRABP-II转录本在热分离的人真皮中也有表达，其水平与在表皮角质层活检中发现的水平相似，而CRABP-I转录本在真皮RNA中无法检测到。CRABP-II转录本在银屑病皮损中显著升高，就像在RA处理的皮肤中一样。相比之下，CRABP-I mRNA在银屑病皮损中无法检测到且没有增加。RAR-γ亚型和RXR的表达在银屑病皮损或RA处理的皮肤中均未检测到明显变化。因此，与CRABP-I、RXR或RAR-γ亚型表达的改变相比，CRABP-II表达的改变似乎更有可能调节RA的皮肤作用。基于这些及其他结果，提出了一个涉及CRABP-II螯合RA来调节RA作用的模型。
