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The TLRs play a key role in host defense against infection and injury, and mounting evidence suggests that these receptors may also play a role in diseases such autoimmunity, atherosclerosis, and cancer. Activation of TLRs on macrophages results in the production of multiple soluble mediators including the key inflammatory cytokines, TNF and IL-6. Thus, the intracellular signaling mechanism by which TLRs signal is a subject of great interest. As well as activating the NF-κB and MAPK pathways, TLR engagement leads to tyrosine kinase activation within minutes. Src family kinases (SFKs) are the largest nonreceptor tyrosine kinase family with nine members: Src, Hck, Lyn, Fyn, Fgr, Blk, Lck, Yes, and Ylk. The role of the SFKs in TLR signaling has been an area of much controversy, with conflicting findings between studies using chemical inhibitors and knockout mice. Using primary human macrophages in combination with adenoviral overexpression and small interfering RNA knockdown studies, we show that the SFK, Hck, has a pre-eminent role in LPS/TLR4-induced TNF and IL-6 production. Hck kinase mediates TLR4-induced transcription of both TNF and IL-6 by a mechanism that involves neither the NF-κB nor the MAPK pathways, but rather leads to AP-1 binding with a complex of c-fos and JunD. These data highlight the importance of Hck as an active component in LPS-induced TLR signaling and suggest the possibility of targeting this kinase for the alleviation of excessive inflammation.

Original publication

DOI

10.4049/jimmunol.1100967

Type

Journal article

Journal

Journal of immunology (Baltimore, Md. : 1950)

Publication Date

12/2011

Volume

187

Pages

6043 - 6051

Addresses

Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Kennedy Institute of Rheumatology, Oxford University, London W6 8LH, United Kingdom.

Keywords

Cells, Cultured, Macrophages, Humans, Tumor Necrosis Factor-alpha, Transcription Factor AP-1, Interleukin-6, Blotting, Western, Enzyme-Linked Immunosorbent Assay, Electrophoretic Mobility Shift Assay, Signal Transduction, Gene Expression, Gene Expression Regulation, RNA Interference, Toll-Like Receptor 4, Proto-Oncogene Proteins c-hck, Real-Time Polymerase Chain Reaction