Interleukin-1 and Tumor Necrosis Factor Alpha Induce Class 1 Aldehyde Dehydrogenase mRNA and Protein in Bone Marrow Cells

Abstract

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.

The Role of Human Aldehyde Dehydrogenase in Normal and Cancer Stem Cells

“…A possible mechanism for the protection of stem cells from drugs such as 4-HC via ALDH1 may be due to interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) [104]. Moreb, et al observed that pre-treatment of bone marrow cells with IL-1 and TNF-α for 6 to 20 hours resulted in an increase in ALDH1 mRNA and protein levels [105], and that this ultimately leads cellular protection against 4-HC [104]. Since then, it has been determined that high cytosolic ALDH1A1 or ALDH3A1 activity in normal cells [106,107], stem cells [44], and cancer stem cells [65,74] confers resistance to therapy in preclinical model systems.…”

Isolation of primitive human hematopoietic progenitors on the basis of aldehyde dehydrogenase activity

“…2 A and B) (32). To test whether BAAA was a substrate for human ALDH, K562 cells were stained with BAAA (28,33). K562 cells stained moderately with BAAA ( Fig.…”

“…ALDH is a cytosolic enzyme that is responsible for oxidizing a variety of aldehydes including vitamin A (24,25). ALDH is expressed at high levels in hematopoietic progenitors and appears to be responsible for the resistance of HSCs to the alkylating agents cyclophosphamide and 4-hydroxyperoxycyclophosphamide (10,(26)(27)(28). Jones et al (22,29) demonstrated proof of the principle for this strategy in the murine system.…”

Human A1, a Bcl-2-related gene, is induced in leukemic cells by cytokines as well as differentiating factors

“…All cell lines were grown in RPMI to be induced by IL-1 and/or TNF␣. 10,11 The overexpression 1640 medium supplemented with 10% fetal calf serum (FCS) of MnSOD and ALDH-1 promotes resistance to radiation and except for HL-60 and KG-1 cells which were grown in IMDM 4-HC, respectively. 12,13 medium supplemented with 20% FCS.…”