IL-4 stimulates mouse macrophages to express APRIL through p38MAPK and two different downstream molecules, CREB and Stat6.
APRIL (a proliferation-inducing ligand) is primarily expressed by macrophages and dendritic cells, and has profound effects on B cell physiology. In this study, we investigated the role of IL-4 in APRIL expression by mouse macrophages and the signaling mechanism involved. IL-4 markedly enhanced APRIL expression in mouse macrophages at the transcriptional and protein level. The p38MAPK inhibitor SB203580 completely abolished the IL-4 effect, whereas overexpression of CREB with IL-4 augmented APRIL expression. This increase was abolished by SB203580 treatment, indicating that p38MAPK may activate CREB. Overexpression of Stat6 also augmented IL-4-induced APRIL expression; this effect was partially abolished by SB203580 but not by the Jak inhibitor AG490, indicating that Stat6 mediates IL-4-induced APRIL expression in a Jak-independent manner and that p38MAPK acts as the intermediate. Our results demonstrate that IL-4 up-regulates APRIL expression through two divergent pathways in mouse macrophages, p38MAPK-CREB and p38MAPK-Stat6.
Department of Molecular Bioscience, School of Bioscience and Biotechnology, Kangwon National University, Chuncheon 200-701, South Korea.
Young-Saeng
YS
Jang
Hyun-A
HA
Kim
Seok-Rae
SR
Park
Mi-Ra
MR
Lee
Jae-Bong
JB
Park
Pyeung-Hyeun
PH
Kim
D000818:Animals; D045744:Cell Line, Tumor; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics*; D015870:Gene Expression / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D050800:STAT6 Transcription Factor / Q000235:genetics*; D015398:Signal Transduction / Q000502:physiology*; D014162:Transfection; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13 / Q000235:genetics / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; C491959:Tnfsf13 protein, mouse; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13; D015847:Interleukin-4; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580