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Chem Biol Interact. 1995 Dec 22;98(3):211-22.

Inhibition of the conversion of pre-interleukins-1 alpha and 1 beta to mature cytokines by p-benzoquinone, a metabolite of benzene.

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1
Department of Biochemistry and Molecular Biology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA 19107, USA.

Abstract

Chronic exposure of humans to benzene causes severe bone marrow cell depression leading to aplastic anemia. Marrow stromal macrophage dysfunction and deficient interleukin-1 production has been reported for patients with severe aplastic anemia. The stromal macrophage, a target of benzene toxicity, is involved in hematopoietic regulation through the synthesis of several cytokines including interleukin-1, which is required for production by stromal fibroblasts of a number of cytokines required for the survival of hematopoietic progenitor cells. We have previously demonstrated that hydroquinone, a major toxic metabolite of benzene in marrow, prevents the proteolytic conversion of 31 kDa pre-interleukin-1 alpha to the 17 kDa cytokine by calpain in purified murine stromal macrophages. Furthermore, stromal macrophages from benzene-treated mice produce the 31 kDa pre-interleukin-1 alpha when stimulated in culture with endotoxin, but cannot convert the precursor to interleukin-1 alpha. In this report, we show that 1,4-benzoquinone, the oxidation product of hydroquinone in the cell, causes a concentration-dependent inhibition of highly purified human platelet calpain with an IC50 of 3 microM. Hydroquinone also inhibits the processing of pre-interleukin-1 beta by interleukin-1 beta convertase. The addition of 2 microM hydroquinone to B1 cells that undergo autocrine stimulation by interleukin-1 beta resulted in the cessation of autocrine cell growth and interleukin-1 beta secretion into the culture medium, as determined by Western immunoblots of the culture supernatants. Purified converting enzyme treated with 3 microM benzoquinone was incapable of converting 31 kDa recombinant pre-interleukin-1 beta to the 17 kDa mature cytokine as analyzed by polyacrylamide gel electrophoresis and Western immunoblotting. These findings support our observations in a mouse model that benzene-induced bone marrow cell depression results from a lack of interleukin-1 alpha subsequent to an inhibition by benzoquinone of calpain, the protease required for converting pre-interleukin-1 alpha to active cytokine. The results may provide a basis for studying benzene-induced aplastic anemia in a mouse model.

PMID:
8548860
[Indexed for MEDLINE]
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