| First Author | Koziczak-Holbro M | Year | 2008 |
| Journal | Eur J Immunol | Volume | 38 |
| Issue | 3 | Pages | 788-96 |
| PubMed ID | 18266302 | Mgi Jnum | J:132115 |
| Mgi Id | MGI:3775150 | Doi | 10.1002/eji.200737886 |
| Citation | Koziczak-Holbro M, et al. (2008) IRAK-4 kinase activity-dependent and -independent regulation of lipopolysaccharide-inducible genes. Eur J Immunol 38(3):788-96 |
| abstractText | IRAK-4 kinase inactive (IRAK-4 KD) knock-in mice display defects in TLR- and IL-1 receptor signaling and are resistant to LPS-induced shock. In the present study we examined the LPS-induced response in IRAK-4 KD mice in more detail. We show that IRAK-4 kinase activity is required for certain aspects of TLR-mediated signaling but not for others. We found that IRAK-4 KD cells displayed reduced JNK and p38 signaling, while NF-kappaB was activated to a normal level but with delayed kinetics compared to wild-type cells. TLR4-mediated IRF3 activation was intact in these cells. Comprehensive analysis of expression of LPS-inducible genes by microarray demonstrated that IRAK-4 KD cells were severely impaired in the expression of many pro-inflammatory genes, suggesting their dependence on IRAK-4 kinase activity. In contrast, the expression of a subset of LPS-induced genes of anti-viral response was not affected by IRAK-4 kinase deficiency. Additionally, we demonstrate that LPS-activated early expression and production of some cytokines, e.g., TNF-alpha, is partially induced in the absence of IRAK-4 kinase activity. This suggests that the partially unaffected TLR4-mediated signaling could still drive expression of these genes in early phases and that IRAK-4 kinase activity is important for a more sustained anti-bacterial response.See accompanying commentary http://dx.doi.org/10.1002/eji.200838161. |
