Background: The influence of genetic polymorphisms of interleukin (IL)-10, tumour necrosis factor (TNF)-α, and IL-6 gene promoters on severity of systemic inflammatory response syndrome (SIRS) associated with community acquired pneumonia (CAP) was studied. Methods: Using PCR-RFLP analysis we analysed a −1082G/A single nucleotide polymorphism (SNP) of the anti-inflammatory IL-10 gene, a −308G/A SNP of the pro-inflammatory TNF-α gene and a −174G/C SNP of the IL-6 gene. Illness severity was stratified according to SIRS score, calculated by presence of up to four physiological indices: temperature, white blood cell count, heart rate and respiratory rate (non-SIRS, SIRS 2, SIRS 3, and SIRS 4). Results: A statistically significant stepwise increase in frequency of the IL-10 G allele, associated with higher expression of the gene, was observed in patients with increasing severity of illness from non-SIRS (n=19) to SIRS 2 (n=17), SIRS 3 (n=33) and SIRS 4 (n=24). This was primarily due to a higher frequency of the GG genotype with increasing severity from non-SIRS through to SIRS 4. IL-10 G allele frequency was also increased in patients who died as a result of CAP (n=11) compared with CAP survivors (n=82) (p=0.01). No association was seen between the TNF-α −308G/A and IL-6 −174G/C SNPs and disease. Additionally, no interaction between all three SNP genotypes and disease severity was observed. Conclusions: A polymorphism affecting IL-10 expression may influence the severity of illness in patients with CAP.

Interleukin‐1 (IL‐1) is a central regulator of the immune and inflammatory responses. Recently, significant advances have been made in the area of IL‐1 receptors and IL‐1 signal transduction. A family of proteins has been described that share significant homology in their signaling domains with the Type I IL‐1 receptor (IL‐1RI). These include the IL‐1 receptor accessory protein (IL‐1AcP), which does not bind IL‐1 but is essential for IL‐1 signaling; a Drosophila protein Toll; a number of human Toll‐like receptors (hTLRs); the putative IL‐18/IL‐1‐γ receptor IL‐1Rrp (IL‐1 receptor‐related protein); and a number of plant proteins. All appear to be involved in host responses to injury and infection. These homologies also extend to novel signaling proteins implicated in IL‐1 action. Two IL‐1 receptor‐associated kinases, IRAK‐1 and IRAK‐2, which have homologs in Drosophila (Pelle) and plants (Pto), have been implicated in the activation of the transcription factor, nuclear factor κB (NF‐κB). IRAK‐1 has also been implicated in AP1 induction, Jun amino‐terminal kinase (JNK) activation, and IL‐2 induction. It recruits the adapter protein TRAF6 to the IL‐1 receptor complex via an interaction with IL‐1AcP. TRAF6 then relays the signal via NF‐κB‐inducing kinase (NIK) to two I‐κB kinases (IKK‐1 and ‐2), leading to NF‐κB activation. Progress has also been made on other IL‐1‐responsive kinases, including JNK and p38 MAP kinase, with the latter having a role in multiple responses to IL‐1. The remarkable conservation between diverse species indicates that the IL‐1 system represents an ancient signaling machine critical for responses to environmental stresses and attack by pathogens. J. Leukoc. Biol. 63: 650–657; 1998.

Secretory leucoprotease inhibitor (SLPI) is a nonglycosylated protein produced by epithelial cells. In addition to its antiprotease activity, SLPI has been shown to exhibit antiinflammatory properties, including down-regulation of tumor necrosis factor α expression by lipopolysaccharide (LPS) in macrophages and inhibition of nuclear factor (NF)-κB activation in a rat model of acute lung injury. We have previously shown that SLPI can inhibit LPS-induced NF-κB activation in monocytic cells by inhibiting degradation of IκBα without affecting the LPS-induced phosphorylation and ubiquitination of IκBα. Here, we present evidence to show that upon incubation with peripheral blood monocytes (PBMs) and the U937 monocytic cell line, SLPI enters the cells, becoming rapidly localized to the cytoplasm and nucleus, and affects NF-κB activation by binding directly to NF-κB binding sites in a site-specific manner. SLPI can also prevent p65 interaction with the NF-κB consensus region at concentrations commensurate with the physiological nuclear levels of SLPI and p65. We also demonstrate the presence of SLPI in nuclear fractions of PBMs and alveolar macrophages from individuals with cystic fibrosis and community-acquired pneumonia. Therefore, SLPI inhibition of NF-κB activation is mediated, in part, by competitive binding to the NF-κB consensus-binding site.