Simultaneous induction of matrix metalloproteinase-9 and interleukin 8 by all-trans retinoic acid in human PL-21 and NB4 myeloid leukaemia cells.
All-trans retinoic acid (ATRA) has been shown to induce differentiation of human acute promyelocytic leukaemia (APL) cells and eventual elimination of the malignant clone. Matrix metalloproteinase-9 (MMP-9) is produced by neutrophils and its expression appears to be linked with myeloid cell differentiation. We investigated effects of ATRA on MMP expression in two human myeloid leukaemia cell lines, PL-21 and NB4. Both cells could differentiate into neutrophils after exposure to ATRA. Both the activity and antigen levels of MMP-9 were much higher in NB4 cells than in PL-21 cells. Stimulation with ATRA significantly increased MMP-9 levels approximately three- to fivefold in both PL-21 and NB4-conditioned media. MMP-9 mRNA levels increased in ATRA-treated cells and was almost in parallel with the increase in MMP-9 activity, suggesting that ATRA induced MMP-9 by activating its gene expression. ATRA can induce interleukin 8 (IL-8) in APL cells. IL-8, chemokine for neutrophils and a potent inducer of MMP-9, was also induced by ATRA in PL-21 cells. However, recombinant IL-8 did not induce MMP-9 expression. In addition, a neutralizing antibody against IL-8 did not inhibit ATRA-induced MMP-9 expression in either cell type. These observations suggest that ATRA can induce both MMP-9 and IL-8, but IL-8 is not involved in ATRA-induced MMP-9 expression. As MMP-9 can truncate and activate IL-8, simultaneous induction of MMP-9 and IL-8 by ATRA could activate leucocytes excessively, causing the hyper-inflammatory events in retinoic acid syndrome.
Department of Health Sciences, Okayama University Medical School, 2-5-1 Shikata-cho, Okayama 700-8558, Japan. m_shiba@md.okayama-u.ac.jp
Misako
M
Shibakura
Kenji
K
Niiya
Toru
T
Kiguchi
Katsuji
K
Shinagawa
Fumihiko
F
Ishimaru
Kazuma
K
Ikeda
Masayoshi
M
Namba
Yasunari
Y
Nakata
Mine
M
Harada
Mitsune
M
Tanimoto
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism*; D007951:Leukemia, Myeloid / Q000188:drug therapy* / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D014212:Tretinoin / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000970:Antineoplastic Agents; D016209:Interleukin-8; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D014212:Tretinoin; D020780:Matrix Metalloproteinase 9