Differential involvement of calmodulin-dependent protein kinase II-activated AP-1 and c-Jun N-terminal kinase-activated EGR-1 signaling pathways in tumor necrosis factor-alpha and lipopolysaccharide-induced CD44 expression in human monocytic cells.
CD44 plays a crucial role in cell migration, inflammation, and immune responses. Alteration in the levels of CD44 expression on monocytic cells by endotoxins and immunoregulatory cytokines may modulate the migration of immune cells to inflammatory sites and the development of immune responses. Lipopolysaccharide (LPS) and the proinflammatory cytokine, tumor necrosis factor-alpha (TNF-alpha), act as important regulators of CD44 expression in human monocytic cells. We previously demonstrated that the c-Jun N-terminal kinase (JNK), a mitogen-activated protein kinase (MAPK), differentially regulated LPS- but not TNF-alpha-induced CD44 expression in monocytic cells. In this study, our results suggest that the calcium signaling pathway, in particular calmodulin (CaM) and CaM-dependent protein kinase II (CaMK-II), is involved in TNF-alpha- but not LPS-induced CD44 expression. CD44 promoter analysis suggested the participation of distinct transcription factors AP-1 and Egr-1 in TNF-alpha- and LPS-induced CD44 expression, respectively. Furthermore, TNF-alpha-induced CD44 expression was regulated by AP-1 through the activation of the CaMK-II pathway, whereas LPS-induced CD44 transcription was regulated specifically by Egr-1 through JNK activation. Overall, the results suggest the involvement of two distinct and independent signaling pathways involved in the regulation of CD44 transcription that may represent potential targets for anti-inflammatory agents capable of inhibiting CD44-mediated cell migration.
Mishra
Jyoti P
JP
Department of Pathology and Laboratory Medicine, University of Ottawa, Ontario, Canada.
Mishra
Sasmita
S
Gee
Katrina
K
Kumar
Ashok
A
D020013:Calcium Signaling; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism* / Q000502:physiology; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000502:physiology; D051766:Early Growth Response Protein 1; D005786:Gene Expression Regulation; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics*; D017874:Immediate-Early Proteins / Q000378:metabolism / Q000502:physiology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism / Q000502:physiology; D008070:Lipopolysaccharides / Q000494:pharmacology; D009000:Monocytes / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000378:metabolism / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism / Q000502:physiology; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D004268:DNA-Binding Proteins; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; D018960:Hyaluronan Receptors; D017874:Immediate-Early Proteins; D008070:Lipopolysaccharides; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases