Activation of src-family tyrosine kinases by LPS regulates cytokine production in dendritic cells by controlling AP-1 formation.
The role of src-family tyrosine kinases in LPS-induced DC maturation has not been fully addressed. We show that LPS induces activation of c-Src and Lyn in human DC. Inhibition of these kinasesby PP1 uncoupled LPS-induced cytokine production from the up-regulation of costimulatory molecules, resulting in DC still capable of stimulating T cell proliferation but much less efficient in inducing Th1 differentiation. This is the first example of a pharmacological inhibitor able to modulate the capacity of DC to induce a particular type of immune response. Inhibition of src-family kinases impaired phosphorylation and accumulation of c-Jun, leading to reduced formation of AP-1 complexes upon LPS stimulation. Thus, src-kinases control cytokine production in LPS-induced DC maturation through a timely formation of AP-1.
D002454:Cell Differentiation; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis*; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D003713:Dendritic Cells / Q000276:immunology*; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D050856:Interferon Regulatory Factor-1; D050835:Interferon Regulatory Factors; D008070:Lipopolysaccharides / Q000494:pharmacology*; D010750:Phosphoproteins / Q000096:biosynthesis; D010766:Phosphorylation; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D054400:Receptors, CCR7; D019707:Receptors, Chemokine / Q000096:biosynthesis; D012097:Repressor Proteins / Q000096:biosynthesis; D018417:Th1 Cells / Q000502:physiology; D018808:Transcription Factor AP-1 / Q000096:biosynthesis*; D015854:Up-Regulation; D019061:src-Family Kinases / Q000378:metabolism*; D000099185:Interferon Regulatory Factor-8
D016207:Cytokines; D004268:DNA-Binding Proteins; D050856:Interferon Regulatory Factor-1; D050835:Interferon Regulatory Factors; D008070:Lipopolysaccharides; D010750:Phosphoproteins; D016755:Proto-Oncogene Proteins c-jun; D054400:Receptors, CCR7; D019707:Receptors, Chemokine; D012097:Repressor Proteins; D018808:Transcription Factor AP-1; D019061:src-Family Kinases; D000099185:Interferon Regulatory Factor-8; C515370:CCR7 protein, human; C494257:IRF1 protein, human