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Isoniazid induces a monocytic-like phenotype in HL-60 cells

Babu, Dinesh, Khan, Saifur R., Srivastava, Nutan, Kyoung Suh, Lindsey Yeon, Morgan, Andrew G., Aljuhani, Naif, Fahlman, Richard P., Siraki, Arno G.
Archives of biochemistry and biophysics 2019 v.664 pp. 15-23
NAD(P)H oxidase (H2O2-forming), NADP (coenzyme), biomarkers, drugs, enzyme activity, esterases, hematopoietic stem cells, humans, isoniazid, leukemia, monocytes, phenotype, proteins, proteomics, signal transduction, tuberculosis, vitamin D
Isoniazid (INH) is one of the oldest drugs for the treatment of tuberculosis (TB) and is of continual clinical and research interest. The aim of the current study is to investigate the ability of INH to induce monocyte differentiation and the underlying signaling pathway involved in this phenomenon using HL-60 cells. In this study, HL-60 cells were treated with different non-cytotoxic concentrations of INH or vitamin D (a well-known inducer of monocytic differentiation) to determine key functional changes in the phenotype of these cells using several biochemical and cytobiological experiments. HL-60 cells are derived from human promyelocytic leukemia and bear some resemblance to promyelocytes, which differentiate into various cell types. INH-induced differentiation was confirmed to occur in a concentration-dependent manner through several functional markers such as nonspecific esterase activity, NADPH oxidase activity and expression of surface markers CD14 and CD16 (characteristic of monocytes). INH-induced monocytic-like differentiation in HL-60 cells and demonstrated that at least 25% of cells were differentiated within the range of the pharmacological concentrations of INH. To determine the effects of INH on HL-60 cells, we applied quantitative proteomics that revealed 32 proteins were altered significantly in pathways that could involve differentiation signals. Lastly, INH activated the ERK-1/MAPK signaling pathway based on detection of phosphorylated ERK-1. These in vitro findings in HL-60 cells warrant further study using promyelocytes or hematopoietic stem cells to evaluate the physiological capability of INH to induce monocytic differentiation that may aid in host defense against TB.