Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.22.36 (caspase-1)
6,285 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

IL-4 and IL-13 are instrumental in the development and progression of allergy and atopic disease. Basophils represent a key source of these cytokines and produce IL-4 and IL-13 when stimulated with IL-18, a member of the IL-1 family of cytokines. Comparative analyses of the effects of caspase-1-dependent IL-1 family cytokines on basophil IL-4 and IL-13 production have not been performed, and the signaling pathway proteins required for FcepsilonRI-independent Th2 cytokine production from basophils remain incompletely defined. Using mouse bone marrow-derived cultured basophils, we found that IL-4 and IL-13 are produced in response to IL-18 or IL-33 stimulation. IL-18- or IL-33-mediated Th2 cytokine production is dependent on MyD88 and p38alpha signaling proteins. In addition, basophil survival increased in the presence of IL-18 or IL-33 as a result of increased Akt activation. Studies in vivo confirmed the potency of IL-18 and IL-33 in activating cytokine release from mouse basophils.
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PMID:IL-18 and IL-33 elicit Th2 cytokines from basophils via a MyD88- and p38alpha-dependent pathway. 1979 2

Proinflammatory cytokines of the IL-1 family play an important role for the anti-mycobacterial host defense mechanisms. In the present study we have deciphered the pathways leading from recognition of Mycobacterium tuberculosis to the production and release of IL-1beta, the most important member of the IL-1 family. By stimulating cells defective in various pattern recognition receptors, we could demonstrate that IL-1beta production is induced by M. tuberculosis through pathways involving TLR2/TLR6 and NOD2 receptors. In contrast, TLR4, TLR9 and TLR1 receptors are not involved in IL-1beta induction. Recognition of M. tuberculosis by TLR and NOD2 leads to transcription of proIL-1beta through mechanisms involving ERK, p38 and Rip2, but not JNK. Interestingly, although caspase-1 is necessary for the processing of proIL-1beta, activation of caspase-1 is not dependent on the stimulation of cells by M. tuberculosis. Monocytes expressed constitutively active caspase-1. The secretion of IL-1beta is dependent on the activation of P2X7-induced pathways by endogenously released ATP. In conclusion, we have dissected the molecular mechanisms responsible for IL-1beta production by M. tuberculosis, and that may contribute to a deeper knowledge of the mechanisms of cell activation by M. tuberculosis.
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PMID:Transcriptional and inflammasome-mediated pathways for the induction of IL-1beta production by Mycobacterium tuberculosis. 1954 85

Interleukin-33 (IL-33) is a member of the IL-1 family and is involved in polarization of T cells toward a T helper 2 (Th2) cell phenotype. IL-33 is thought to be activated via caspase-1-dependent proteolysis, similar to the proinflammatory cytokines IL-1 beta and IL-18, but this remains unproven. Here we showed that IL-33 was processed by caspases activated during apoptosis (caspase-3 and -7) but was not a physiological substrate for caspases associated with inflammation (caspase-1, -4, and -5). Furthermore, caspase-dependent processing of IL-33 was not required for ST2 receptor binding or ST2-dependent activation of the NF-kappaB transcription factor. Indeed, caspase-dependent proteolysis of IL-33 dramatically attenuated IL-33 bioactivity in vitro and in vivo. These data suggest that IL-33 does not require proteolysis for activation, but rather, that IL-33 bioactivity is diminished through caspase-dependent proteolysis within apoptotic cells. Thus, caspase-mediated proteolysis acts as a switch to dampen the proinflammatory properties of IL-33.
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PMID:Suppression of interleukin-33 bioactivity through proteolysis by apoptotic caspases. 1960 86

Bacterial infection elicits a range of beneficial as well as detrimental host inflammatory responses. Key among these responses are macrophage/monocyte necrosis, release of the proinflammatory factor high-mobility group box 1 protein (HMGB1), and induction of the cytokine IL-1. Although the control of IL-1beta has been well studied, processes that control macrophage cell death and HMGB1 release in animals are poorly understood. This study uses Klebsiella pneumonia as a model organism because it elicits all three responses in vivo. The regulation of these responses is studied in the context of the inflammasome components NLRP3 and ASC, which are important for caspase-1 activation and IL-1beta release. Using a pulmonary infection model that reflects human infection, we show that K. pneumonia-induced mouse macrophage necrosis, HMGB1, and IL-1beta release are dependent on NLRP3 and ASC. K. pneumoniae infection of mice lacking Nlrp3 results in decreased lung inflammation and reduced survival relative to control, indicating the overall protective role of this gene. Macrophage/monocyte necrosis and HMGB1 release are controlled independently of caspase-1, suggesting that the former two responses are separable from inflammasome-associated functions. These results provide critical in vivo validation that the physiologic role of NLRP3 and ASC is not limited to inflammasome formation.
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PMID:NLRP3 (NALP3, Cryopyrin) facilitates in vivo caspase-1 activation, necrosis, and HMGB1 release via inflammasome-dependent and -independent pathways. 1958 6

Interleukin (IL)-33 is a novel member of the IL-1 family. IL-33 is primarily synthesized as a 30-kDa precursor (pro-IL-33). Pro-IL-33 is cleaved by caspase-1 into an 18-kDa mature form (mature IL-33) in vitro. Recombinant mature IL-33 has been known to induce T-helper type-2 (Th2)-associated cytokines and inflammatory cytokines via its receptor, ST2L. However, processing of pro-IL-33 in vivo has not been clarified yet. Here, we report that calpain mediates pro-IL-33 processing in vivo. Pro-IL-33 was expressed by stimulating human epithelial cells with phorbol 12-myristate 13-acetate. Calcium ionophore induced pro-IL-33 cleavage and mature IL-33 production. This cleavage was inhibited by treatment with a calcium chelator and calpain inhibitors. Moreover, short interfering RNA-mediated knockdown of calpains suppressed pro-IL-33 cleavage. These results indicate that calpains play a critical role in pro-IL-33 processing in vivo.
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PMID:Mature interleukin-33 is produced by calpain-mediated cleavage in vivo. 1959 70

The therapeutic efficacy of anticancer chemotherapies may depend on dendritic cells (DCs), which present antigens from dying cancer cells to prime tumor-specific interferon-gamma (IFN-gamma)-producing T lymphocytes. Here we show that dying tumor cells release ATP, which then acts on P2X(7) purinergic receptors from DCs and triggers the NOD-like receptor family, pyrin domain containing-3 protein (NLRP3)-dependent caspase-1 activation complex ('inflammasome'), allowing for the secretion of interleukin-1beta (IL-1beta). The priming of IFN-gamma-producing CD8+ T cells by dying tumor cells fails in the absence of a functional IL-1 receptor 1 and in Nlpr3-deficient (Nlrp3(-/-)) or caspase-1-deficient (Casp-1(-/-)) mice unless exogenous IL-1beta is provided. Accordingly, anticancer chemotherapy turned out to be inefficient against tumors established in purinergic receptor P2rx7(-/-) or Nlrp3(-/-) or Casp1(-/-) hosts. Anthracycline-treated individuals with breast cancer carrying a loss-of-function allele of P2RX7 developed metastatic disease more rapidly than individuals bearing the normal allele. These results indicate that the NLRP3 inflammasome links the innate and adaptive immune responses against dying tumor cells.
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PMID:Activation of the NLRP3 inflammasome in dendritic cells induces IL-1beta-dependent adaptive immunity against tumors. 2239 93

The mevalonate kinase deficiency (MKD), including hyperimmunoglobulinemia D periodic fever syndrome (HIDS) and the more severe mevalonic aciduria are rare, autosomal recessive, autoinflammatory diseases belonging to the hereditary periodic fever (HPF) family. Other members include: familial mediterranean fever (FMF), the cryopyrin-associated periodic syndromes (CAPS) and TNFR-associated periodic syndromes (TRAPS). MKD is caused by mutations in the gene encoding mevalonate kinase (MK), an enzyme of the cholesterol pathway, leading to its inactivation. The molecular mechanisms linking MKD and abnormalities of isoprenoid biosynthesis to cytokine production and inflammation have yet to be fully elucidated. Statins, which are extensively prescribed for lowering cholesterol, are potent inhibitors of 3-hydroxy-3-methylglutaryl-CoA reductase, the enzyme directly upstream of MK. In this review, we discuss recent reports demonstrating that in vitro inhibition of the mevalonate pathway by statins specifically increases the production, by activated monocytes, of cytokines of the IL-1 family, by enhancing caspase-1 activity, the enzyme responsible for IL-1beta and IL-18 maturation. The molecular mechanisms involve geranylgeranylation and the enhancement of the activity of G proteins such as Rac-1. Interestingly, activated fibroblasts from MKD patients secrete more IL-1beta than fibroblasts from healthy donors. Taken together, these data highlight the specific enhancement of the IL-1 family of cytokines, the maturation of which is caspase-1-dependent in MKD. Finally, the spectacular decrease in febrile attacks in patients with severe HIDS under IL-1 receptor antagonist (anakinra) treatment, reinforces this hypothesis. Deregulated caspase-1 activation could be responsible for the inflammatory component of MKD, thereby mechanistically linking MKD to FMF and CAPS through cytokines of the IL-1 family.
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PMID:Specific increase in caspase-1 activity and secretion of IL-1 family cytokines: a putative link between mevalonate kinase deficiency and inflammation. 1982 18

Schnitzler syndrome is a rare disease characterised by chronic urticaria and arthralgia. The recent evidence that the IL-1 receptor antagonist IL-1Ra could induce rapid and complete remission of Schnitzler symptoms has pointed to IL-1 as a major pathological factor in this disease. To examine the possibility that Schnitzler syndrome may be considered to be an autoinflammatory disease, in this study we measured the serum levels of IL-18, another cytokine of the IL-1 family that is cleaved by caspase-1, in two recently diagnosed Schnitzler patients before and after treatment with IL-1Ra. In parallel, mRNA expression of IL-1 family cytokines and caspase-1 were assessed in isolated blood monocytes. Treatment with IL-1Ra significantly inhibited IL-1beta gene expression, indicating that IL-1beta activity in Schnitzler syndrome is central to IL-1beta gene upregulation in a type of auto-amplification loop. While no IL-1beta was detected in serum, free circulating IL-18 was increased in patients with Schnitzler syndrome, despite low IL-18 gene expression in monocytes. This suggests constitutive activation of the IL-1beta/IL-18-producing inflammasome, and supports the hypothesis that Schnitzler's syndrome is a new autoinflammatory disease.
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PMID:Free circulating interleukin-18 is increased in Schnitzler syndrome: a new autoinflammatory disease? 1982 19

Thalidomide is an efficient anti-inflammatory and anti-angiogenic drug, but its therapeutic use is problematic due to a strong teratogenic activity. Nevertheless, thalidomide was approved for the treatment of inflammatory skin diseases and certain types of cancer, and it is extensively tested for several other indications. Recently, we demonstrated that active caspase-1, whose activation is dependent on inflammasome complexes, is required for unconventional protein secretion of proinflammatory cytokines such as IL-1 and of the proangiogenic fibroblast growth factor 2. In this study, we show that pharmacological doses of thalidomide strongly reduced the secretion of both proteins. Thalidomide-treated cells also released less of other leaderless proteins, which require caspase-1 activity for their secretion. In line with these findings, the drug inhibited activation and activity of caspase-1 in cultured cells but not in vitro. The latter finding suggests that the pharmacological activity is exerted by a metabolite of the drug. The anti-inflammatory activity of thalidomide was also mediated via caspase-1 in mice. These findings represent a novel mechanism by which thalidomide exerts its pharmacological activity and suggest that inhibition of the activity of IL-1 might represent a novel strategy to substitute thalidomide.
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PMID:Thalidomide inhibits activation of caspase-1. 1984 43

Tibia fracture followed by limb immobilization in rats evokes nociceptive and vascular changes resembling complex regional pain syndrome type I (CRPS I). Previously we observed that substance P (SP) and interleukin-1beta (IL-1beta) signaling contribute to chronic regional nociceptive sensitization in this model. It is known that inflammasome multi-protein complexes containing caspase-1 and NALP1 are involved in the activation of the IL-1beta family of pro-nociceptive cytokines expressed in skin and other tissues. Therefore, we hypothesized that SP activated inflammasomes might contribute to mechanical allodynia after fracture. Using this model we observed that: (1) inflammasome components and products NALP1, caspase-1, IL-1beta and IL-18 were present in low levels in normal skin, but expression of all these was strongly up-regulated after fracture, (2) NALP1, caspase-1 and IL-1beta were co-expressed in keratinocytes, and the number of NALP1, caspase-1, and IL-1beta positive cells dramatically increased at 4 weeks post-fracture, (3) LY303870, an NK1 receptor antagonist, effectively blocked fracture-induced up-regulation of activated inflammasome components and cytokines, (4) IL-1beta and IL-18 intraplantar injection induced mechanical allodynia in normal rats, and (5) both a selective caspase-1 inhibitor and an IL-1 receptor antagonist attenuated fracture-induced hindpaw mechanical allodynia. Collectively, these data suggest that NALP1 containing inflammasomes activated by NK1 receptors are expressed in keratinocytes and contribute to post-traumatic regional nociceptive sensitization. These findings highlight the possible importance of neuro-cutaneous signaling and innate immunity mechanisms in the development of CRPS.
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PMID:The NALP1 inflammasome controls cytokine production and nociception in a rat fracture model of complex regional pain syndrome. 1985 79


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