Benzene-induced bone marrow cell depression caused by inhibition of the conversion of pre-interleukins-1alpha and -1beta to active cytokines by hydroquinone, a biological reactive metabolite of benzene.

Abstract

Benzene (BZ), a widely used industrial chemical and a ubiquitous environmental pollutant, is a hematotoxin that causes bone marrow (BM) cell depression in experimental animals and aplastic anemia in humans that are chronically exposed1-3. Marrow stromal macrophage (SO) dysfunction and deficient interleukin-1 (IL-1) production have been demonstrated in aplastic anemia. Markedly depressed IL-1 production was observed in adherence-separated, LPS-stimulated monocytes from 75 to 80 percent of patients with severe aplastic anemia compared with normal control subjects4,5. The SO is involved in hematopoietic regulation6–8 through the synthesis of several cytokines including IL-1, which synergizes with IL-3 to promote the development of the pluripotent stem cell to myeloid and lymphoid stem cells9. IL-1 is also involved in lymphocyte development and in the induction of cytokine production by stromal fibroblasts8,10,11. Inhibition of the production of active IL-1 in SO could result in a lack of cytokines, increased apoptosis of hematopoietic progenitor cells and thus aplastic anemia. Two IL-1 cytokines, IL-1 α and IL-1 β, are the products of distinct genes located on chromosome 212. The transcript of each gene is translated as a precursor protein of approximately 34 kDa that is converted by a specific protease to a biologically active cytokine of 17 kDa13. The processing of pre-IL-1α to mature cytokine is catalyzed by the calcium-activated, cysteine protease, calpain14,15. The release of IL-1β from the cell is also associated with the cleavage of its precursor form by a sulfhydryl-dependent protease referred to as IL-1β convertase (ICE)16–18.