Robust TLR4-induced gene expression patterns are not an accurate indicator of human immunity | Brown et al. Journal of Translational Medicine 2010 8 6 http content 8 1 6 JOURNAL OF TRANSLATIONAL MEDICINE RESEARCH Open Access Robust TLR4-induced gene expression patterns are not an accurate indicator of human immunity Kelly L Brown1 2 4 Reza Falsafi 1 Winnie Kum1 Pamela Hamill1 Jennifer L Gardy1 Donald J Davidson2 3 Stuart Turvey2 Brett B Finlay1 David P Speert2 Robert EW Hancock1 Abstract Background Activation of Toll-like receptors TLRs is widely accepted as an essential event for defence against infection. Many TLRs utilize a common signalling pathway that relies on activation of the kinase IRAK4 and the transcription factor NFkB for the rapid expression of immunity genes. Methods 21 K DNA microarray technology was used to evaluate LPS-induced TLR4 gene responses in blood monocytes from a child with an IRAK4-deficiency. In vitro responsiveness to LPS was confirmed by real-time PCR and ELISA and compared to the clinical predisposition of the child and IRAK4-deficient mice to Gram negative infection. Results We demonstrated that the vast majority of LPS-responsive genes in IRAK4-deficient monocytes were greatly suppressed an observation that is consistent with the described role for IRAK4 as an essential component of TLR4 signalling. The severely impaired response to LPS however is inconsistent with a remarkably low incidence of Gram negative infections observed in this child and other children with IRAK4-deficiency. This unpredicted clinical phenotype was validated by demonstrating that IRAK4-deficient mice had a similar resistance to infection with Gram negative S. typhimurium as wildtype mice. A number of immunity genes such as chemokines were expressed at normal levels in human IRAK4-deficient monocytes indicating that particular IRAK4-independent elements within the repertoire of TLR4-induced responses are expressed. Conclusions Sufficient defence to Gram negative immunity does not require IRAK4 or a robust classic .
