Familial cold autoinflammatory syndrome (FCAS) is an autosomal dominant disorder characterised by recurrent episodes of rash, arthralgia, and fever after cold exposure. The genetic basis of this disease has been elucidated. Cryopyrin, the protein that is altered in FCAS, is one of the adaptor proteins that activate caspase 1, resulting in release of interleukin 1.
An experimental cold challenge protocol was developed to study the acute inflammatory mechanisms occurring after a general cold exposure in FCAS patients and to investigate the effects of pretreatment with an antagonist of interleukin 1 receptor (IL-1Ra). ELISA, real-time PCR, and immunohistochemistry were used to measure cytokine responses.
After cold challenge, untreated patients with FCAS developed rash, fever, and arthralgias within 1-4 h. Significant increases in serum concentrations of interleukin 6 and white-blood-cell counts were seen 4-8 h after cold challenge. Serum concentrations of interleukin 1 and cytokine mRNA in peripheral-blood leucocytes were not raised, but amounts of interleukin 1 protein and mRNA were high in affected skin. IL-1Ra administered before cold challenge blocked symptoms and increases in white-blood-cell counts and serum interleukin 6.
The ability of IL-1Ra to prevent the clinical features and haematological and biochemical changes in patients with FCAS indicates a central role for interleukin 1beta in this disorder. Involvement of cryopyrin in activation of caspase 1 and NF-kappaB signalling suggests that it might have a role in many chronic inflammatory diseases.
These findings support a new therapy for a disorder with no previously known acceptable treatment. They also offer insights into the role of interleukin 1beta in more common inflammatory diseases.
"Circulating IL-6 levels were significantly higher in CRMO patients during active disease. In cryopirinopathies, in which abnormal IL-1 secretion drives the cytokine cascade and all clinical and laboratory features, IL-6 production in tissues and high circulating levels have been shown to be completely IL-1β dependent [10,18]. "
[Show abstract][Hide abstract] ABSTRACT: Background
This study aims to investigate the inflammasome response in peripheral blood mononuclear cells (PBMCs) and the expression of inflammasome components in bone biopsies from patients with chronic recurrent multifocal osteomyelitis (CRMO).
The expression of inflammasome components mRNAs was evaluated in PBMCs isolated from 15 CRMO patients and 13 healthy controls by quantitative real-time PCR. The Interleukin (IL)-1β released in the medium of PBMC cultures after treatment with lipopolysaccharides (LPS) alone or LPS and ATP was measured by ELISA. Immunohistochemical staining for Apoptosis-associated Speck-like protein (ASC), caspase-1 (CASP-1), Nod-like receptor protein-3 (NLRP3) and IL-1β expression was performed in bone biopsies from CRMO patients.
mRNA levels of ASC, CASP-1 and IL-1β were significantly higher in freshly isolated PBMCs from CRMO patients in active disease than in healthy controls. CASP-1 and IL-1β transcript levels were significantly higher also in PBMCs from CRMO patients in remission compared to healthy controls. PBMCs from CRMO patients in active disease stimulated in vitro with LPS showed a significant increase in IL-1β release compared to healthy control cells. Immunohistochemistry staining of bone tissue revealed the expression of inflammasome components in CRMO osteoclasts.
Our data suggest that an abnormal regulation of IL-1β axis may be involved in CRMO pathogenesis.
"Infection with the PVL+ strain was associated with greater IL-1β release in the BALF than was the case with a ΔPVL mutant strain (Fig. 3A). This cytokine is notoriously difficult to detect in biological fluids  suggesting that the low levels of IL-1β detected in the BALF of PVL+
S. aureus infected rabbits were probably biologically relevant. As previously described , PVL+
S. aureus-mediated pneumonia was associated with a greater increase in IL-8 levels in the BALF (Fig. 3B) and the lung lysates than that observed during infection with the ΔPVL strain (Fig. 3C). "
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Community-acquired Staphylococcus aureus necrotizing pneumonia is a life-threatening disease. Panton Valentine Leukocidin (PVL) has been associated with necrotizing pneumonia. PVL triggers inflammasome activation in human macrophages leading to IL-1β release. IL-1β activates lung epithelial cells to release IL-8. This study aimed to assess the relevance of this inflammatory cascade in vivo and to test the potential of an IL-1 receptor antagonist (IL-1Ra/Kineret) to decrease inflammation-mediated lung injury.
We used the sequential instillation of Heat-killed S. aureus and PVL or S. aureus infection to trigger necrotizing pneumonia in rabbits. In these models, we investigated inflammation in the presence or absence of IL-1Ra/Kineret.
We demonstrated that the presence of PVL was associated with IL-1β and IL-8 release in the lung. During PVL-mediated sterile pneumonia, Kineret/IL-1Ra reduced IL-8 production indicating the relevance of the PVL/IL-1/IL-8 cascade in vivo and the potential of Kineret/IL-1Ra to reduce lung inflammation. However, Kineret/IL-1Ra was ineffective in blocking IL-8 production during infection with S. aureus. Furthermore, treatment with Kineret increased the bacterial burden in the lung.
Our data demonstrate PVL-dependent inflammasome activation during S.aureus pneumonia, indicate that IL-1 signaling controls bacterial burden in the lung and suggest that therapy aimed at targeting this pathway might be deleterious during pneumonia.
PLoS ONE 06/2014; 9(6):e97546. DOI:10.1371/journal.pone.0097546 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Inherited autoinflammatory diseases are secondary to mutations of proteins playing a pivotal role in the regulation of the innate immunity leading to seemingly unprovoked episodes of inflammation. The understanding of the molecular pathways involved in these disorders has shed new lights on the pattern of activation and maintenance of the inflammatory response and disclosed new molecular therapeutic targets. Cryopyrin-associated periodic syndrome (CAPS) represents the prototype of an autoinflammatory disease. The study of the pathophysiological consequence of mutations in the cryopyrin gene (NLRP3) allowed the identification of intracellular pathways responsible for the activation and secretion of the potent inflammatory cytokine interleukin-1β (IL-1β). It became clear that several multi-factorial inflammatory conditions display a number of pathogenic and clinical similarities with inherited autoinflammatory diseases. The dramatic effect of interleukin-1 (IL-1) blockade in CAPS opened new perspectives for the treatment of other inherited and multi-factorial autoinflammatory disorders. Several IL-1 blockers are now available on the market. In this review we outline the more recent novelties in the treatment with different IL-1 blockers in inherited and multi-factorial autoinflammatory diseases.
Frontiers in Immunology 10/2013; 4:351. DOI:10.3389/fimmu.2013.00351
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