All-trans retinoic acid down-regulates expression and function of beta2 integrins by human monocytes: opposite effects on monocytic cell lines.

Abstract

All-trans retinoic acid (ATRA) plays an important role in the differentiation of malignant myeloid cells but its effects on primary leukocytes have been poorly investigated. We report here that ATRA negatively affects expression and function of leukocyte integrins that play a key role in monocyte adhesive interactions. As evidenced by flow cytometry, ATRA (at 1 microM) clearly and donor-independently suppressed the expression of all integrin chains investigated (CD11a, CD11b, CD11c, and CD18), most strikingly of CD11a. Down-regulation was detectable after 24 and maximal after 72-96 h. Reverse transcription-PCR analysis revealed diminished steady-state concentrations of alpha specific transcripts but not of the common beta chain, suggesting that heterodimer expression was predominantly regulated through alpha chains. Results obtained with blood-derived monocytes were in sharp contrast to those for the leukemic cell lines THP-1 and U937, both of which showed marked increase in all integrin subunits in response to ATRA. ATRA-pretreated monocytes displayed significantly diminished beta(2) integrin-dependent homotypic aggregation, and adhesion to stimulated endothelial cells (EC), while ATRA-pretreated monocytic cell lines showed the opposite behavior displaying markedly enhanced aggregation and CD18-mediated adhesion to EC. Therefore, the level of leukocyte integrins was obviously a decisive factor for these adhesive interactions irrespective of the cellular source. Collectively, our data indicate a striking difference between leukemic cell lines and normal hematopoietic cells with regard to ATRA responsiveness. By acting on key adhesive structures of normal leukocytes, ATRA mediates processes that may be of substantially broad range applying to inflammation and immunity in addition to differentiation and proliferation.