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Indirubin, a Chinese anti‐leukaemia drug, promotes neutrophilic differentiation of human myelocytic leukaemia HL‐60 cells
Author(s) -
Suzuki Kazuhiro,
Adachi Reiko,
Hirayama Akiko,
Watanabe Hidemi,
Otani Saki,
Watanabe Yuka,
Kasahara Tadashi
Publication year - 2005
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/j.1365-2141.2005.05655.x
Subject(s) - indirubin , microbiology and biotechnology , chemistry , biology , cancer research , art , visual arts , indigo
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 β 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.