IngentaConnect Indirubin, a Chinese anti-leukaemia drug, promotes neutrophilic d...

Authors: Suzuki, Kazuhiro¹; Adachi, Reiko¹; Hirayama, Akiko; Watanabe, Hidemi; Otani, Saki; Watanabe, Yuka; Kasahara, Tadashi²

Source: British Journal of Haematology, Volume 130, Number 5, September 2005 , pp. 681-690(10)

Publisher: Blackwell Publishing

Abstract:

Summary

Indirubin, a purple vegetable dye, is a traditional Chinese medicine for myelocytic leukaemia. Indirubin inhibits cyclin-dependent protein kinases (CDKs) and is present in human urine and serum. When indirubin was present during the neutrophilic differentiation of human myelocytic leukaemia HL-60 cells, it augmented superoxide production triggered by opsonized zymosan (OZ) by the terminally differentiated HL-60 cells. It also augmented the calcium response to OZ stimulation, and HL-60 cell chemotaxis evoked by interleukin-8 (IL-8, CXCL8) and formylpeptide. In addition, indirubin induced marked IL-8 release by the cells during differentiation and the cells differentiated with indirubin had typical neutrophilic properties, deformed nuclei and granules. Use of stable cloned HL-60 cells that contained a reporter vector for monitoring the activity of the transcription factor PU.1, which acts specifically at the stage of promyelocyte differentiation into neutrophils and monocytes, revealed that indirubin has a potent promoting activity on intracellular PU.1. Indirubin enhanced the expression of typical neutrophil proteins, including granulocyte-colony stimulating factor receptor, the ₂-integrin subunit CD18, the NADPH-oxidase subunit p47phox, and the IL-8 receptor CXCR1, all are controlled by PU.1. Indirubin also inhibited CDK2-dependent phosphorylation of retinoblastoma protein during neutrophilic differentiation. These results suggest that indirubin augments the neutrophilic differentiation of human myelocytic leukaemia HL-60 cells through inhibition of CDK2 and activation of PU.1.

Keywords: IL-8 (CXCL8); calcium response; superoxide; chemotaxis; retinoblastoma protein

Document Type: Research article

DOI: 10.1111/j.1365-2141.2005.05655.x

Affiliations: 1: National Institute of Health Sciences, Tokyo, Japan 2: Kyoritsu University of Pharmacy, Tokyo, Japan

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Indirubin, a Chinese anti-leukaemia drug, promotes neutrophilic differentiation of human myelocytic leukaemia HL-60 cells