Robust TLR4-induced gene expression patterns are not an accurate indicator of human immunity.
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 NFkappaB 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' inflammatory and immune response.
Brown
Kelly L
KL
Centre for Microbial Diseases and Immunity Research, Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia, V6T 1Z3, Canada. kelly.brown@rheuma.gu.se
Falsafi
Reza
R
Kum
Winnie
W
Hamill
Pamela
P
Gardy
Jennifer L
JL
Davidson
Donald J
DJ
Turvey
Stuart
S
Finlay
Brett B
BB
Speert
David P
DP
Hancock
Robert E W
RE
D000818:Animals; D018925:Chemokines / Q000276:immunology; D002648:Child; D016207:Cytokines / Q000276:immunology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D007109:Immunity / Q000235:genetics / Q000276:immunology; D053592:Interleukin-1 Receptor-Associated Kinases / Q000235:genetics / Q000276:immunology*; D008070:Lipopolysaccharides / Q000276:immunology / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D016328:NF-kappa B / Q000276:immunology; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction / Q000379:methods; D012486:Salmonella typhimurium / Q000276:immunology / Q000472:pathogenicity; D015398:Signal Transduction / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology
D018925:Chemokines; D016207:Cytokines; D008070:Lipopolysaccharides; D016328:NF-kappa B; D051197:Toll-Like Receptor 4; C507773:IRAK4 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases