Activation of src‐family tyrosine kinases by LPS regulates cytokine production in dendritic cells by controlling AP‐1 formation

• Published in: European journal of immunology Vol. 33; no. 10; pp. 2832 - 2841
• Main Authors: Napolitani, Giorgio, Bortoletto, Nicola, Racioppi, Luigi, Lanzavecchia, Antonio, D'Oro, Ugo
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY‐VCH Verlag 01-10-2003
• Subjects: Cell Differentiation; Cells, Cultured; Cytokines - biosynthesis; Dendritic cell; Dendritic Cells - immunology; DNA-Binding Proteins - biosynthesis; Enzyme Activation - drug effects; Humans; Interferon Regulatory Factor-1; Interferon Regulatory Factors; Lipopolysaccharides - pharmacology; LPS; Lyn protein; Phosphoproteins - biosynthesis; Phosphorylation; Proto-Oncogene Proteins c-jun - metabolism; Receptors, CCR7; Receptors, Chemokine - biosynthesis; Repressor Proteins - biosynthesis; Src kinase; Src protein; src-Family Kinases - metabolism; Th1 Cells - physiology; Transcription Factor AP-1 - biosynthesis; Up-Regulation
• ISSN: 0014-2980; 1521-4141
• DOI: 10.1002/eji.200324073

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.