Dexamethasone suppresses interleukin-1beta-induced human beta-defensin 2 mRNA expression: involvement of p38 MAPK, JNK, MKP-1, and NF-kappaB transcriptional factor in A549 cells.
Human beta-defensin (HBD)-2 is an inducible antimicrobial peptide that plays an important role in innate immunity. Glucocorticoids, on the other hand, exert immunosuppressive and anti-inflammatory actions. We have previously reported that interleukin (IL)-1beta induces HBD-2 mRNA expression through the activation of nuclear factor-kappaB (NF-kappaB) transcriptional factor, as well as p38 mitogen-activated protein kinase (MAPK), c-Jun N-terminal kinase (JNK), or phosphatidylinositol-3-kinase/AKT in A549 cells. In this study, we further investigated whether dexamethasone (Dex) controls IL-1beta-induced HBD-2 mRNA expression in A549 cells and the molecular mechanism associated with it. Dex suppressed IL-1beta-induced HBD-2 mRNA expression, which is mediated by a glucocorticoid receptor, at the transcriptional level. Interestingly, Dex attenuated IL-1beta-mediated activation of p38 MAPK and JNK, but not of AKT. Dex increased the expression of MAPK phosphatase (MKP)-1, which dephosphorylated p38 MAPK, but not JNK, by IL-1beta. However, although Dex did not inhibit the nuclear translocation of p65 NF-kappaB in response to IL-1beta, it profoundly inhibited NF-kappaB promoter- and HBD-2 promoter-driven luciferase activities. These results suggest that Dex acts to inhibit IL-1beta-induced HBD-2 mRNA expression through blockage of the nuclear transcriptional activation of p65 NF-kappaB as well as through inactivation of p38 MAPK and JNK. Specifically, Dex-induced MKP-1 expression is responsible for the inactivation of p38 MAPK, but not JNK, in response to IL-1beta in A549 cells.
Jang
Byeong-Churl
BC
Chronic Disease Research Center and Institute for Medical Science, School of Medicine Keimyung University, Daegu, Korea.
Lim
Ki-Jo
KJ
Suh
Min-Ho
MH
Park
Jong-Gu
JG
Suh
Seong-Il
SI
D018797:Cell Cycle Proteins / Q000502:physiology*; D002460:Cell Line; D003907:Dexamethasone / Q000494:pharmacology*; D054638:Dual Specificity Phosphatase 1; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D017874:Immediate-Early Proteins / Q000502:physiology*; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors*; D048031:JNK Mitogen-Activated Protein Kinases / Q000502:physiology*; D016328:NF-kappa B / Q000502:physiology*; D010749:Phosphoprotein Phosphatases / Q000502:physiology*; D010766:Phosphorylation; D054645:Protein Phosphatase 1; D017027:Protein Tyrosine Phosphatases / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D012333:RNA, Messenger / Q000032:analysis; D023083:beta-Defensins / Q000235:genetics*; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology*
D018797:Cell Cycle Proteins; C106641:DEFB4A protein, human; D017874:Immediate-Early Proteins; D053583:Interleukin-1beta; D016328:NF-kappa B; D012333:RNA, Messenger; D023083:beta-Defensins; D003907:Dexamethasone; D051057:Proto-Oncogene Proteins c-akt; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; C517019:DUSP1 protein, human; D054638:Dual Specificity Phosphatase 1; D017027:Protein Tyrosine Phosphatases