Growth potentiating activity of endogenous production of interleukin-1 and tumor necrosis factor alpha in blast cells of acute myeloblastic leukemia.
For the optimal growth of clonogenic cells in acute myeloblastic leukemia (AML), several cytokines such as tumor necrosis factor alpha (TNF-alpha), interleukin-1 (IL-1) and IL-6 are required in addition to colony-stimulating factor (CSF), which may be produced by blast cells themselves. In the present study, we addressed the potential role of endogenous production of TNF-alpha and/or IL-1 in the in vitro growth of AML clonogenic cells supported by IL-3. Addition of a specific neutralizing antibody against TNF-alpha (anti-TNF-alpha) to the culture significantly reduced the growth-stimulating effect of IL-3 on the cells in 11 of 14 patients. Simultaneous addition of anti-IL-1 alpha and anti-IL-1 beta also partly affected the growth, although to a much lesser extent when compared to the effect observed with anti-TNF-alpha. In 3 patients, the growth-stimulating effect of IL-3 was completely abrogated by anti-TNF-alpha or a combination of all three antibodies. Constitutive TNF-alpha transcript was observed in 5 patients and TNF-alpha protein was present in culture supernatant. Following in vitro culture, a transient but profound increase in c-fos, c-jun, TNF-alpha and IL-1 beta mRNA levels was observed. Anti-TNF-alpha inhibited the accumulation of TNF-alpha transcript, suggesting that membrane-integrated TNF-alpha may be partly responsible for the induction of TNF-alpha mRNA. It seems likely that the accumulation of these genes occurs through a protein kinase C-independent signaling pathway.
Murohashi
I
I
Department of Laboratory Medicine, Tokyo Medical and Dental University, Japan.
Tohda
S
S
Imai
Y
Y
Hirai
Y
Y
Nara
N
N
D000906:Antibodies; D002455:Cell Division; D015870:Gene Expression; D016762:Genes, fos; D016758:Genes, jun; D006801:Humans; D007375:Interleukin-1 / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D007377:Interleukin-3 / Q000494:pharmacology; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism* / Q000473:pathology*; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology
D000906:Antibodies; D007375:Interleukin-1; D007377:Interleukin-3; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha