Activation of interleukin-1 beta gene expression during retinoic acid-induced granulocytic differentiation of promyeloid leukemia cells.

ABSTRACT

We have examined the expression of the interleukin 1 beta (IL-1 beta) gene during the granulocytic differentiation of two promyeloid leukemia cell lines, HL-60 and NB4. HL-60 is known to differentiate along the granulocytic pathway after treatment with 13-trans-retinoic acid (13-trans-RA), whereas treatment with phorbol myristate acetate (PMA) leads to development of mature macrophages. NB4 cells are derived from the bone marrow of an acute promyelocytic leukemia (APL) patient in relapse, have a translocated RA receptor-alpha, and are converted into nondividing granulocytes by 13-trans-RA treatment. When HL-60 or NB4 were cultured in the presence of 13-trans-RA, IL-1 beta mRNA and protein levels were increased. In the more mature THP-1 cells which are induced to macrophage-like cells by 13-trans-RA treatment, RA was unable to induce any IL-1 beta expression, implying that the effect of 13-trans-RA is associated with granulocytic differentiation. Moreover, PMA and 13-trans-RA had a strong synergistic effect in the induction of IL-1 beta gene expression. Nuclear run-off analysis indicated that the increased IL-1 beta gene expression was due to an enhanced rate of transcription. When the cells were transfected with an IL-1 beta-X-CAT reporter plasmid containing the -2982/-2748 promoter segment of the IL-1 beta gene conferring responsiveness to PMA, both NB4 and HL-60 cells responded with increased CAT activity when stimulated with 13-trans-RA alone. In contrast to PMA, 13-trans-RA was unable to increase AP-1 enhancer activity.(ABSTRACT TRUNCATED AT 250 WORDS)