Differential effects of interleukin-3 and interleukin-1 on the proliferation and interleukin-6 protein secretion of acute myeloid leukemic cells; the involvement of ERK, p38 and STAT5.
In the present study we examined whether the p38 and extracellular signal-regulated kinase (ERK) signal transduction pathways are involved in the interleukin-3 (IL-3)- or interleukin-1 (IL-1)-mediated proliferation and cytokine production of acute myeloid leukemic (AML) cells. The IL-3- and IL-1-mediated proliferation were both inhibited by the specific p38 and MEK1 inhibitors SB203580 and PD98059, respectively. Specificity of these inhibitors was demonstrated by in vitro kinase assays. Furthermore, we examined whether STAT5 (signal transducer and activator of transcription) activity is modulated by the p38 and ERK signal transduction pathways, since STAT5 activation has been linked to proliferation. We provide evidence that the p38 kinase pathway, but not the ERK pathway, is to a certain degree involved in the modulation of STAT5 transactivation since SB203580 and overexpression of an inactive MKK3 mutant inhibited the IL-3-induced STAT5 reporter transactivation. In addition, the p38 and ERK pathways are also involved in cytokine production. The IL-1-enhanced IL-6 protein secretion was strongly reduced by SB203580 and PD98059. Despite the fact that IL-3 did induce p38 and ERK kinase activity, it was not able to enhance IL-6 protein secretion, which coincided with the inability of IL-3 to induce NFkappaB (nuclear factor kappaB) activation and IkappaB (inhibitory protein kappaB) degradation. This study demonstrates that the p38 and ERK pathways play a functional role in cell proliferation and IL-6 secretion of AML cells which are dependent on the activated cytokine receptors.
Birkenkamp
K U
KU
Division of Hematology, Department of Medicine, University Hospital Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands.
Esselink
M T
MT
Kruijer
W
W
Vellenga
E
E
D000208:Acute Disease; D002455:Cell Division / Q000187:drug effects; D004247:DNA / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D007377:Interleukin-3 / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D015850:Interleukin-6 / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins; D007951:Leukemia, Myeloid / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008894:Milk Proteins; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D050799:STAT5 Transcription Factor; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects; D014407:Tumor Cells, Cultured; D048051:p38 Mitogen-Activated Protein Kinases; D000099190:MAP-Kinase-Activated Kinase 2
D004247:DNA; D004268:DNA-Binding Proteins; D005419:Flavonoids; D020672:I-kappa B Proteins; D007093:Imidazoles; D007375:Interleukin-1; D007377:Interleukin-3; D015850:Interleukin-6; D047908:Intracellular Signaling Peptides and Proteins; D008894:Milk Proteins; D020929:Mitogen-Activated Protein Kinase Kinases; D020928:Mitogen-Activated Protein Kinases; D016328:NF-kappa B; D017346:Protein Serine-Threonine Kinases; D011725:Pyridines; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; D048051:p38 Mitogen-Activated Protein Kinases; D000099190:MAP-Kinase-Activated Kinase 2; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one