During acute inflammation, leukocyte recruitment is characterized by an initial infiltration of neutrophils, which are later replaced by a more sustained population of mononuclear cells. Based on both clinical and experimental evidence, we present a role for IL-6 and its soluble receptor (sIL-6R) in controlling this pattern of leukocyte recruitment during peritoneal inflammation. Liberation of sIL-6R from the initial neutrophil infiltrate acts as a regulator of CXC and CC chemokine expression, which contributes to a suppression of neutrophil recruitment and the concurrent attraction of mononuclear leukocytes. Soluble IL-6R-mediated signaling is therefore an important intermediary in the resolution of inflammation and supports transition between the early predominantly neutrophilic stage of an infection and the more sustained mononuclear cell influx.

Severe acute respiratory syndrome coronavirus (SARS-CoV) is a highrisk infectious pathogen. In the proposed model of respiratory failure, SARS-CoV down-regulates its receptor, angiotensin-converting enzyme 2 (ACE2), but the mechanism involved is unknown. We found that the spike protein of SARS-CoV (SARS-S) induced TNF-␣-converting enzyme (TACE)-dependent shedding of the ACE2 ectodomain. The modulation of TACE activity by SARS-S depended on the cytoplasmic domain of ACE2, because deletion mutants of ACE2 lacking the carboxyl-terminal region did not induce ACE2 shedding or TNF-␣ production. In contrast, the spike protein of HNL63-CoV (NL63-S), a CoV that uses ACE2 as a receptor and mainly induces the common cold, caused neither of these cellular responses. Intriguingly, viral infection, judged by real-time RT-PCR analysis of SARS-CoV mRNA expression, was significantly attenuated by deletion of the cytoplasmic tail of ACE2 or knock-down of TACE expression by siRNA. These data suggest that cellular signals triggered by the interaction of SARS-CoV with ACE2 are positively involved in viral entry but lead to tissue damage. These findings may lead to the development of anti-SARS-CoV agents.shedding ͉ cytoplasmic tail ͉ HNL63-CoV ͉ TNF-␣ S evere acute respiratory syndrome coronavirus (SARS-CoV) is an infectious pathogen known to have caused acute respiratory distress in Ͼ8,000 patients with a mortality rate of Ϸ10% (1). Although outbreaks of SARS-CoV are now well controlled, the mechanism of severe respiratory failure in infected patients is unknown. Angiotensin-converting enzyme 2 (ACE2), an ACE homolog that functions as a positive regulator of the reninangiotensin system (RAS) (2, 3), was identified as a receptor of SARS-CoV (4). A possible indicator of a severe clinical outcome, the spike protein of SARS-CoV (SARS-S) was found to downregulate ACE2 expression (5). ACE2 knockout (KO) mice were also shown to be susceptible to severe respiratory failure after chemical challenge (5, 6), and ACE2 has been shown to moderate ACE-induced intracellular inflammation, suggesting that the mechanism of ACE2 down-regulation may explain the molecular basis of SARS-CoV-related severe respiratory distress.HNL63-CoV, a CoV (7) that causes the common cold, was recently found to use ACE2 for viral infection (8), and it was further shown that the spike protein of HNL63-CoV (NL63-S) binds ACE2 directly (9). NL63-S and SARS-S show 21% identity (10), whereas that between NL63-S and the spike protein of HCoV-229E, which uses CD13 [a completely different carboxy (C)-peptidase] as a cellular receptor (11), is 55%. It is important to note that, despite their phylogenetically distinct properties and their producing different clinical outcomes, SARS-CoV and HNL63-CoV both use ACE2.Based on these observations, we hypothesized that the functional modulation of ACE2 may be differentially induced by SARS-S and NL63-S. To test this prediction, we first clarified the mechanism of SARS-S-induced ACE2 down-regulation, and then compared the cellular respon...

Neutrophils contribute to pathogen clearance by producing neutrophil extracellular traps (NETs), which are genomic DNA-based net-like structures that capture bacteria and fungi. Although NETs also express antiviral factors, such as myeloperoxidase and α-defensin, the involvement of NETs in antiviral responses remains unclear. We show that NETs capture human immunodeficiency virus (HIV)-1 and promote HIV-1 elimination through myeloperoxidase and α-defensin. Neutrophils detect HIV-1 by Toll-like receptors (TLRs) TLR7 and TLR8, which recognize viral nucleic acids. Engagement of TLR7 and TLR8 induces the generation of reactive oxygen species that trigger NET formation, leading to NET-dependent HIV-1 elimination. However, HIV-1 counteracts this response by inducing C-type lectin CD209-dependent production of interleukin (IL)-10 by dendritic cells to inhibit NET formation. IL-10 suppresses the reactive oxygen species-dependent generation of NETs induced upon TLR7 and TLR8 engagement, resulting in disrupted NET-dependent HIV-1 elimination. Therefore, NET formation is an antiviral response that is counteracted by HIV-1.

Toll-like receptors (TLRs) recognize microbial components and trigger the inflammatory and immune responses against pathogens. IkappaBzeta (also known as MAIL and INAP) is an ankyrin-repeat-containing nuclear protein that is highly homologous to the IkappaB family member Bcl-3 (refs 1-6). Transcription of IkappaBzeta is rapidly induced by stimulation with TLR ligands and interleukin-1 (IL-1). Here we show that IkappaBzeta is indispensable for the expression of a subset of genes activated in TLR/IL-1R signalling pathways. IkappaBzeta-deficient cells show severe impairment of IL-6 production in response to a variety of TLR ligands as well as IL-1, but not in response to tumour-necrosis factor-alpha. Endogenous IkappaBzeta specifically associates with the p50 subunit of NF-kappaB, and is recruited to the NF-kappaB binding site of the IL-6 promoter on stimulation. Moreover, NF-kappaB1/p50-deficient mice show responses to TLR/IL-1R ligands similar to those of IkappaBzeta-deficient mice. Endotoxin-induced expression of other genes such as Il12b and Csf2 is also abrogated in IkappaBzeta-deficient macrophages. Given that the lipopolysaccharide-induced transcription of IkappaBzeta occurs earlier than transcription of these genes, some TLR/IL-1R-mediated responses may be regulated in a gene expression process of at least two steps that requires inducible IkappaBzeta.

Interleukin 6 (IL-6) performs a prominent role during disease and has been described as both a pro- and anti-inflammatory cytokine. A key feature in the regulation of IL-6 responses has been the identification of a soluble interleukin 6 receptor (sIL-6R), which forms a ligand-receptor complex with IL-6 that is capable of stimulating a variety of cellular responses including proliferation, differentiation and activation of inflammatory processes. Elevated sIL-6R levels have been documented in numerous clinical conditions indicating that its production is coordinated as part of a disease response. Thus, sIL-6R has the potential to regulate both local and systemic IL-6-mediated events. This review will outline the central role of sIL-6R in the coordination of IL-6 responses. Details relating to the mechanisms of sIL-6R production will be provided, while the potential significance of sIL-6R during the development of clinical conditions will be emphasized. We want to convey, therefore, that when thinking about the inflammatory capability of IL-6, it is essential to consider not only the action of IL-6 itself, but also the effect sIL-6R may have on cellular processes.