Distinct mutations in IRAK-4 confer hyporesponsiveness to lipopolysaccharide and interleukin-1 in a patient with recurrent bacterial infections.

We identified previously a patient with recurrent bacterial infections who failed to respond to gram-negative LPS in vivo, and whose leukocytes were profoundly hyporesponsive to LPS and IL-1 in vitro. We now demonstrate that this patient also exhibits deficient responses in a skin blister model of aseptic inflammation. A lack of IL-18 responsiveness, coupled with diminished LPS and/or IL-1-induced nuclear factor-kappaB and activator protein-1 translocation, p38 phosphorylation, gene expression, and dysregulated IL-1R-associated kinase (IRAK)-1 activity in vitro support the hypothesis that the defect lies within the signaling pathway common to toll-like receptor 4, IL-1R, and IL-18R.

Regulation of lipopolysaccharide sensitivity by IFN regulatory factor-2.

IFN regulatory factors (IRFs) are a family of transcription factors and include several members that regulate expression of pro- and anti-inflammatory genes. Mice with a targeted mutation in IRF-2 (IRF-2(-/-)) were studied after injection of LPS to evaluate the importance of IRF-2 in the regulation of endotoxicity. IRF-2(-/-) mice were highly refractory to LPS-induced lethality.

The role of the interferon regulatory factors, IRF-1 and IRF-2, in LPS-induced cyclooxygenase-2 (COX-2) expression in vivo and in vitro.

Cyclooxygenase (COX) exists as two isoforms: COX-1, which is constitutively expressed in most cell types; and COX-2, which is inducible by lipopolysaccharide (LPS) and cytokines in a variety of cell types. Although previous studies have implicated two DNA binding proteins, interferon regulatory factor (IRF)-1 and IRF-2, in the regulation of LPS- and IFN-gamma-induced COX-2, their effects in vivo and in vitro are not well-defined. Using real-time PCR, COX-2 gene expression in the livers and lungs of mice challenged in vivo and in macrophages stimulated with LPS in vitro was investigated in wild-type and in IRF-1 and IRF-2 knockout mice.

Induction of early inflammatory gene expression in a murine model of nonresuscitated, fixed-volume hemorrhage.

The etiology of many end-organ problems associated with hemorrhage has been attributed to the inflammatory response to hemorrhage. In a murine model of nonresuscitated, fixed-volume hemorrhage, we sought to elucidate the role that hemorrhagic insult alone plays in the generation of the early inflammatory cascade. Differences could be appreciated as early as 1 h post-hemorrhage, with consistent differences detected by 3 h in all of the major cytokine genes studied.

Signaling by toll-like receptor 2 and 4 agonists results in differential gene expression in murine macrophages.

Lipopolysaccharide (LPS) derived from the periodontal pathogen Porphyromonas gingivalis has been reported to differ structurally and functionally from enterobacterial LPS. These studies demonstrate that in contrast to protein-free enterobacterial LPS, a similarly purified preparation of P. gingivalis LPS exhibited potent Toll-like receptor 2 (TLR2), rather than TLR4, agonist activity to elicit gene expression and cytokine secretion in murine macrophages and transfectants.