Interleukin receptor-associated kinase-4 deficiency impairs Toll-like receptor–dependent innate antiviral immune responses - 20/08/11
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Boston, Mass
Abstract |
Background |
Engagement of all known Toll-like receptors (TLRs) causes the production of inflammatory cytokines, including TNF-⍺, whereas in humans, engagement of TLRs 3, 7, 8, and 9 also induces type I IFNs. IRAK-4 is a critical effector in signaling by TLRs and the IL-1 receptor, which share homology in their intracellular domain and recruit IRAK-4 via the adaptor myeloid differentiation factor 88 (MyD88). Patients with IRAK-4 deficiency are susceptible to invasive bacterial infections but have so far not been reported to be susceptible to viral infection. Blood cells from these patients are impaired in their ability to make TNF-⍺ in response to activation by TLRs. A recent report has described concomitant impairment of type I IFN production after activation of TLRs 7, 8, and 9, but not TLR3.
Objectives |
We sought to evaluate the role of IRAK-4 in TLR-induced production of the type I IFN, IFN-⍺, in humans.
Methods |
We examined TLR-induced production of TNF-⍺ and IFN-⍺ in PBMCs from an IRAK-4–deficient patient, his heterozygous carrier parents, and normal controls.
Results |
TNF-⍺ production in response to TLR agonists was severely impaired in the patient. IFN-⍺ production induced by TLR7, TLR8, and TLR9, as well as TLR3 agonists, was low or absent.
Conclusions |
IRAK-4 plays an important role in the production of type I IFN, as well as TNF-⍺, induced by all TLRs, including TLR3.
Clinical implications |
IRAK-4 may play a broader role in human innate antiviral immunity than previously appreciated.
Le texte complet de cet article est disponible en PDF.Key words : IRAK-4, Toll-like receptor, TNF-⍺, IFN-⍺, Pneumococcus, MyD88, TRIF
Abbreviations used : DC, IL-1R, IRAK-4, MAPK, NF-κB, PAMP, PMA, TLR
Plan
Supported by National Institutes of Health grants P01AI035714 (RSG) and T32AI0075512 (DRM). Disclosure of potential conflict of interest: The authors have declared that they have no conflict of interest. |
Vol 118 - N° 6
P. 1357-1362 - décembre 2006 Retour au numéroBienvenue sur EM-consulte, la référence des professionnels de santé.
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