INTERLEUKIN-1 AND TUMOR-NECROSIS-FACTOR-ALPHA INDUCE CLASS-1 ALDEHYDEDEHYDROGENASE MESSENGER-RNA AND PROTEIN IN BONE-MARROW CELLS

Interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF alpha) prote ct normal human hematopoietic progenitors from the toxicity of 4-hydro peroxycyclophosphamide (4-HC). Aldehyde dehydrogenase Class I (ALDH-1) is the enzyme that inactivates 4-HC. Diethylaminobenzaldehyde (DEAB), a competitive inhibitor of ALDH-1, was shown to prevent the protectiv e effects of IL-1 and TNF alpha. In this study, we examined the effect of IL-1 and TNF alpha on the expression of ALDH-1 in normal bone marr ow as well as malignant cells. ALDH-1 mRNA and protein were quantified using Northern and Western blotting, respectively, In addition, the A LDH-1 enzyme activity in untreated as well as IL-1 and TNF alpha treat ed bone marrow cells was determined spectrophotometrically. The role o f glutathione (GSH) in the protection against 4-HC toxicity was also s tudied. The results show that pretreatment with IL-1 and TNF alpha for 6 h or 20 h increase the expression of ALDH-I mRNA and protein, respe ctively, in human bone marrow cells. In contrast, IL-1 and TNF alpha t reatment did not affect the ALDH-1 expression in several leukemic and solid tumor cell lines, regardless of whether or not ALDH-1 is express ed constitutively. Furthermore, the ALDH-1 enzyme activity was signifi cantly induced in bone marrow cells after 20 h pre-treatment with IL-1 and TNF alpha. Finally, the depletion of or inactivation of GSH did n ot affect the protection against 4-HC toxicity. In conclusion, inhibit ion of the protection from 4-HC toxicity by DEAB, together with the in crease in ALDH-1 expression and activity, provide strong evidence that IL-1 and TNF alpha mediate their protective action, at least partiall y, through ALDH-1.