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

Abstract

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 kinases by 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 cJun, leading to reduced formation of AP-1 complexes upon LPS stimulation. Thus, srckinases control cytokine production in LPS-induced DC maturation through a timely formation of AP-1.

Cyclic AMP Modulates the Functional Plasticity of Immature Dendritic Cells by Inhibiting Src-like Kinases through Protein Kinase A-mediated Signaling

“…A crosstalk between TRAF proteins and c-Src was found in the signaling cascade triggered by TRANCE, a critical regulator of dendritic cell and osteoclast function, and by IL-1 (42,43). According to the recent evidence provided by Napolitani et al (44), our data confirm the role of the Src family tyrosine kinases in the mechanism regulating the release of the cytokines (44). The ability of cAMP to inhibit c-Src and Lyn activity corroborates this hypothesis, identifying for the first time the Src family kinases as targets of the cAMP-dependent pathway in human DCs.…”

Lyn-Dependent Signaling Regulates the Innate Immune Response by Controlling Dendritic Cell Activation of NK Cells

“…In mast cells, Lyn phosphorylates the membrane protein Cbp, leading to signal inhibition and reduction in degranulation (12). Alternatively, positive regulation occurs when Lyn phosphorylates ITAMs on membrane proteins such as Iga/b and CD19, which recruit proteins such as Syk and phospholipase Cg2 that amplify signaling (11,(13)(14)(15) (23)(24)(25)(26), and studies using pan-SFK inhibitors have implicated SFKs in LPS-induced responses in DCs (24,27) and Mfs (28)(29)(30). We and others have shown that Lyn 2/2 bone marrow-derived DCs (BMDCs) are impaired with respect to LPS-induced maturation and IL-12 secretion, suggesting a positive regulatory role for Lyn in LPS-induced DC activation (31,32).…”

TLR4 Signaling Is Coupled to SRC Family Kinase Activation, Tyrosine Phosphorylation of Zonula Adherens Proteins, and Opening of the Paracellular Pathway in Human Lung Microvascular Endothelia

“…The operative PTK(s) and their EC-EC junctional substrates were unknown. LPS has been shown to activate multiple PTKs, including Bruton's tyrosine kinase (27,28), SRC family PTKs (SFKs) (29,30), proline-rich tyrosine kinase 2 (31), Syk (32), and Ron receptor tyrosine kinase (33). LPS increases tyrosine phosphorylation of multiple host proteins, including several components of specialized intercellular junctions, such as connexin 43 and PECAM-1 (34,35).…”