Moreb J S, Turner C, Sreerama L, Zucali J R, Sladek N E, Schweder M
Department of Medicine, University of Florida, Gainesville 32610-0277, USA.
Leuk Lymphoma. 1995 Dec;20(1-2):77-84. doi: 10.3109/10428199509054756.
Interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF alpha) protect normal human hematopoietic progenitors from the toxicity of 4-hydroperoxycyclophosphamide (4-HC). Aldehyde dehydrogenase Class 1 (ALDH-1) is the enzyme that inactivates 4-HC. Diethylaminobenzaldehyde (DEAB), a competitive inhibitor of ALDH-1, was shown to prevent the protective 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 marrow as well as malignant cells. ALDH-1 mRNA and protein were quantified using Northern and Western blotting, respectively. In addition, the ALDH-1 enzyme activity in untreated as well as IL-1 and TNF alpha treated bone marrow cells was determined spectrophotometrically. The role of glutathione (GSH) in the protection against 4-HC toxicity was also studied. The results show that pretreatment with IL-1 and TNF alpha for 6 h or 20 h increase the expression of ALDH-1 mRNA and protein, respectively, in human bone marrow cells. In contrast, IL-1 and TNF alpha treatment did not affect the ALDH-1 expression in several leukemic and solid tumor cell lines, regardless of whether or not ALDH-1 is expressed constitutively. Furthermore, the ALDH-1 enzyme activity was significantly 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 not affect the protection against 4-HC toxicity. In conclusion, inhibition of the protection from 4-HC toxicity by DEAB, together with the increase in ALDH-1 expression and activity, provide strong evidence that IL-1 and TNF alpha mediate their protective action, at least partially, through ALDH-1.
