PMC5438978_01
Regulation of IL-1/18 production and current IL-1/18 antagonists. Pathogen- and danger-associated molecular patterns can induce the formation of a functional inflammasome via events including mitochondrial stress with release of oxidized mtDNA, ROS, lysosomal destabilization with cathepsin B release, changes in intracellular calcium (Ca2+) and potassium (K+) efflux. Also, mutations of NACHT-PYD domains of NLRP3 in cryopyrin-associated periodic syndromes (CAPS) lead to the activation of the NLRP3 inflammasome. Similarly, mutations of B30.2 domains in familial Mediterranean fever (FMF) and of PSTPIP1 in PAPA syndrome or accumulation of geranylgeranylated proteins (GG-proteins) in mevalonate kinase deficiency (MKD) lead to activation of the pyrin inflammasome. Activated inflammasomes recruit procaspase-1 via the adaptor ASC. Autocatalytically cleaved and activated caspase-1 can then process IL-1beta and IL-18. The secreted cytokines bind to the IL-1 receptor (IL-1R1:IL-1RaP) and IL-18 receptor (IL-18Ralpha:IL-18Rbeta), respectively, resulting in NF-kappaB and MAPKs signaling. Soluble IL-1R1 (sIL-1R1), IL-1R2 and IL-18 binding protein (IL-18BP) can block the signaling pathway. Caspase-1 activity can be modulated by the specific inhibitors Pralnacasan and Belnacasan. The activation of the NLRP3 inflammasome can be inhibited with Glibenclamide and curcumin inhibiting or downregulating the ATP-sensitive K+-channels P2X7, respectively; with Resveratrol increasing autophagy and inhibiting mitochondrial stress; and with the specific NLRP3 inhibitors MCC950 and BHB. Anakinra and the secreted IL-1 receptor antagonist (IL-1Ra), absent in deficiency of IL-1 receptor antagonist (DIRA) patients, compete with IL-1beta and IL-1alpha (not shown) for binding to the IL-1 receptor. Rilonacept acts as a soluble decoy binding IL-1beta and with lower affinity IL-1alpha (not shown) and IL-1Ra. The recombinant antibodies Canakinumab, Gevokizumab, LY2189102, and P2D7KK specifically target and neutralize IL-1beta. Similarly, GSK-1070806 and MABp1 inhibits IL-18 and IL-1alpha (not shown), respectively. Blue arrows: inhibitory effect; dotted arrow: low affinity; ASC, apoptosis associated speck-like domain protein containing a CARD; MSU, monosodium urate; mtDNA, mitochondrial DNA; ROS, reactive oxygen species.
fphar-08-00278-g001.jpg
PMC5438978_03_fphar-08-00278-g001.jpg
F1
The resulting mutated protein interacts with, and activates pyrin, causing dysregulated processing of IL-1beta and IL-18 (; Figure 1).
PMC5438978_02
Regulation of IL-1/18 production and current IL-1/18 antagonists. Pathogen- and danger-associated molecular patterns can induce the formation of a functional inflammasome via events including mitochondrial stress with release of oxidized mtDNA, ROS, lysosomal destabilization with cathepsin B release, changes in intracellular calcium (Ca2+) and potassium (K+) efflux. Also, mutations of NACHT-PYD domains of NLRP3 in cryopyrin-associated periodic syndromes (CAPS) lead to the activation of the NLRP3 inflammasome. Similarly, mutations of B30.2 domains in familial Mediterranean fever (FMF) and of PSTPIP1 in PAPA syndrome or accumulation of geranylgeranylated proteins (GG-proteins) in mevalonate kinase deficiency (MKD) lead to activation of the pyrin inflammasome. Activated inflammasomes recruit procaspase-1 via the adaptor ASC. Autocatalytically cleaved and activated caspase-1 can then process IL-1beta and IL-18. The secreted cytokines bind to the IL-1 receptor (IL-1R1:IL-1RaP) and IL-18 receptor (IL-18Ralpha:IL-18Rbeta), respectively, resulting in NF-kappaB and MAPKs signaling. Soluble IL-1R1 (sIL-1R1), IL-1R2 and IL-18 binding protein (IL-18BP) can block the signaling pathway. Caspase-1 activity can be modulated by the specific inhibitors Pralnacasan and Belnacasan. The activation of the NLRP3 inflammasome can be inhibited with Glibenclamide and curcumin inhibiting or downregulating the ATP-sensitive K+-channels P2X7, respectively; with Resveratrol increasing autophagy and inhibiting mitochondrial stress; and with the specific NLRP3 inhibitors MCC950 and BHB. Anakinra and the secreted IL-1 receptor antagonist (IL-1Ra), absent in deficiency of IL-1 receptor antagonist (DIRA) patients, compete with IL-1beta and IL-1alpha (not shown) for binding to the IL-1 receptor. Rilonacept acts as a soluble decoy binding IL-1beta and with lower affinity IL-1alpha (not shown) and IL-1Ra. The recombinant antibodies Canakinumab, Gevokizumab, LY2189102, and P2D7KK specifically target and neutralize IL-1beta. Similarly, GSK-1070806 and MABp1 inhibits IL-18 and IL-1alpha (not shown), respectively. Blue arrows: inhibitory effect; dotted arrow: low affinity; ASC, apoptosis associated speck-like domain protein containing a CARD; MSU, monosodium urate; mtDNA, mitochondrial DNA; ROS, reactive oxygen species.
fphar-08-00278-g001.jpg
PMC5438978_03_fphar-08-00278-g001.jpg
F1
The resulting mutated protein interacts with, and activates pyrin, causing dysregulated processing of IL-1beta and IL-18 (; Figure 1).
PMC5438978_03
Regulation of IL-1/18 production and current IL-1/18 antagonists. Pathogen- and danger-associated molecular patterns can induce the formation of a functional inflammasome via events including mitochondrial stress with release of oxidized mtDNA, ROS, lysosomal destabilization with cathepsin B release, changes in intracellular calcium (Ca2+) and potassium (K+) efflux. Also, mutations of NACHT-PYD domains of NLRP3 in cryopyrin-associated periodic syndromes (CAPS) lead to the activation of the NLRP3 inflammasome. Similarly, mutations of B30.2 domains in familial Mediterranean fever (FMF) and of PSTPIP1 in PAPA syndrome or accumulation of geranylgeranylated proteins (GG-proteins) in mevalonate kinase deficiency (MKD) lead to activation of the pyrin inflammasome. Activated inflammasomes recruit procaspase-1 via the adaptor ASC. Autocatalytically cleaved and activated caspase-1 can then process IL-1beta and IL-18. The secreted cytokines bind to the IL-1 receptor (IL-1R1:IL-1RaP) and IL-18 receptor (IL-18Ralpha:IL-18Rbeta), respectively, resulting in NF-kappaB and MAPKs signaling. Soluble IL-1R1 (sIL-1R1), IL-1R2 and IL-18 binding protein (IL-18BP) can block the signaling pathway. Caspase-1 activity can be modulated by the specific inhibitors Pralnacasan and Belnacasan. The activation of the NLRP3 inflammasome can be inhibited with Glibenclamide and curcumin inhibiting or downregulating the ATP-sensitive K+-channels P2X7, respectively; with Resveratrol increasing autophagy and inhibiting mitochondrial stress; and with the specific NLRP3 inhibitors MCC950 and BHB. Anakinra and the secreted IL-1 receptor antagonist (IL-1Ra), absent in deficiency of IL-1 receptor antagonist (DIRA) patients, compete with IL-1beta and IL-1alpha (not shown) for binding to the IL-1 receptor. Rilonacept acts as a soluble decoy binding IL-1beta and with lower affinity IL-1alpha (not shown) and IL-1Ra. The recombinant antibodies Canakinumab, Gevokizumab, LY2189102, and P2D7KK specifically target and neutralize IL-1beta. Similarly, GSK-1070806 and MABp1 inhibits IL-18 and IL-1alpha (not shown), respectively. Blue arrows: inhibitory effect; dotted arrow: low affinity; ASC, apoptosis associated speck-like domain protein containing a CARD; MSU, monosodium urate; mtDNA, mitochondrial DNA; ROS, reactive oxygen species.
fphar-08-00278-g001.jpg
PMC5438978_03_fphar-08-00278-g001.jpg
F1
The resulting mutated protein interacts with, and activates pyrin, causing dysregulated processing of IL-1beta and IL-18 (; Figure 1).
PMC5438978_04