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.