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Requirement for specific cytosolic tyrosine residues of human TLR7 and TLR8 for signaling by the Immune Response Modifiers.
Author(s) -
Rajagopal Raj,
Mendoza James D.,
Waller Andrew S.,
Wightman Paul D.
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a112-a
Subject(s) - tlr7 , tyrosine , tyrosine kinase , signal transduction , immune system , receptor tyrosine kinase , biology , reporter gene , microbiology and biotechnology , cytosol , sh2 domain , proto oncogene tyrosine protein kinase src , chemistry , biochemistry , toll like receptor , gene , gene expression , immunology , innate immune system , enzyme
The immune response modifiers (IRM) represented by the imidazoquinolines imiquimod and resiquimod are potent regulators of gene expression in mammalian cells and they modulate host response by production of cytokines such as TNF‐alpha and IL12 as well as IFN‐alpha and IFN‐beta. IRMs have been shown to signal through TLR7 and TLR8; however, the signaling pathway for imidazoquinolines through TLR7 and 8 is not clearly understood. As TLR7 and TLR8 contain several tyrosine residues in the cytoplasmic domain, we investigated the potential role of these tyrosine residues by conservatively mutating them to phenylalanine. Based on tansfection assays using a reporter gene driven by NF‐kB promoter, we have identified specific cytosolic tyrosine residues to be essential for TLR7 and TLR8 signaling. Some inhibitors of tyrosine kinases blocked the activation of TLR7 and TLR8 driven NF‐kB reporter by IRMs, further validating the role tyrosine residues in TLR7 and TLR8 signaling.