1.Corosolic acid ameliorates acute inflammation through inhibition of IRAK-1 phosphorylation in macrophages.
Kim SJ, Cha JY, Kang HS, Lee JH, Lee JY, Park JH, Bae JH, Song DK, Im SS1. BMB Rep. 2015 Nov 30. pii: 3403. [Epub ahead of print]
Corosolic acid (CA), a triterpenoid compound isolated from Lagerstroemia speciosa L. (Banaba) leaves, exerts anti-inflammatory effects by regulating phosphorylation of interleukin receptor-associated kinase (IRAK)-2 via the NF-κB cascade. However, the protective effect of CA against endotoxic shock has not been reported. LPS (200 ng/mL, 30 min) induced phosphorylation of IRAK-1 and treatment with CA (10 µM) significantly attenuated this effect. In addition, CA also reduced protein levels of NLRP3 and ASC which are the main components of the inflammasome in BMDMs. LPS-induced inflammasome assembly through activation of IRAK-1 was down-regulated by CA challenge. Treatment with Bay11-7082, an inhibitor of IκB-α, had no effect on CA-mediated inhibition of IRAK-1 activation, indicating that CA-mediated attenuation of IRAK-1 phosphorylation was independent of NF-κB signaling. These results demonstrate that CA ameliorates acute inflammation in mouse BMDMs and CA may be useful as a pharmacological agent to prevent against acute inflammation.
2.The structure function of the death domain of human IRAK-M.
Du J, Nicolaes GA, Kruijswijk D, Versloot M, van der Poll T, van 't Veer C. Cell Commun Signal. 2014 Dec 7;12:77. doi: 10.1186/s12964-014-0077-3.
BACKGROUND: IRAK-M is an inhibitor of Toll-like receptor signaling that acts by re-directing IRAK-4 activity to TAK1 independent NF-κB activation and by inhibition of IRAK-1/IRAK-2 activity. IRAK-M is expressed in monocytes/macrophages and lung epithelial cells. Lack of IRAK-M in mice greatly improves the resistance to nosocomial pneumonia and lung tumors, which entices IRAK-M as a potential therapeutic target. IRAK-M consists of an N-terminal death domain (DD), a dysfunctional kinase domain and unstructured C-terminal domain. Little is known however on IRAK-M's structure-function relationships.
3.The IRAK-ERK-p67phox-Nox-2 axis mediates TLR4, 2-induced ROS production for IL-1β transcription and processing in monocytes.
Singh A1, Singh V1, Tiwari RL1, Chandra T2, Kumar A3, Dikshit M1, Barthwal MK1. Cell Mol Immunol. 2015 Aug 31. doi: 10.1038/cmi.2015.62. [Epub ahead of print]
In monocytic cells, Toll-like receptor 4 (TLR4)- and TLR2-induced reactive oxygen species (ROS) cause oxidative stress and inflammatory response; however, the mechanism is not well understood. The present study investigated the role of interleukin-1 receptor-associated kinase (IRAK), extracellular signal-regulated kinase (ERK), p67phox and Nox-2 in TLR4- and TLR2-induced ROS generation during interleukin-1 beta (IL-1β) transcription, processing, and secretion. An IRAK1/4 inhibitor, U0126, PD98059, an NADPH oxidase inhibitor (diphenyleneiodonium (DPI)), and a free radical scavenger (N-acetyl cysteine (NAC))-attenuated TLR4 (lipopolysaccharide (LPS))- and TLR2 (Pam3csk4)-induced ROS generation and IL-1β production in THP-1 and primary human monocytes. An IRAK1/4 inhibitor and siRNA-attenuated LPS- and Pam3csk4-induced ERK-IRAK1 association and ERK phosphorylation and activity. LPS and Pam3csk4 also induced IRAK1/4-, ERK- and ROS-dependent activation of activator protein-1 (AP-1), IL-1β transcription, and IL-1β processing because significant inhibition in AP-1 activity, IL-1β transcription, Pro- and mature IL-β expression, and caspase-1 activity was observed with PD98059, U0126, DPI, NAC, an IRAK1/4 inhibitor, tanshinone IIa, and IRAK1 siRNA treatment.
4.Renoprotective effects of novel interleukin-1 receptor-associated kinase 4 inhibitor AS2444697 through anti-inflammatory action in 5/6 nephrectomized rats.
Kondo M1, Tahara A, Hayashi K, Abe M, Inami H, Ishikawa T, Ito H, Tomura Y. Naunyn Schmiedebergs Arch Pharmacol. 2014 Oct;387(10):909-19. doi: 10.1007/s00210-014-1023-z. Epub 2014 Jul 23.
Renal inflammation is a final common pathway of chronic kidney disease (CKD), and its progression can be used to effectively gauge the degree of renal dysfunction. Interleukin-1 (IL-1) receptor-associated kinase 4 (IRAK-4) has been reported to be a pivotal molecule for IL-1 receptor- and Toll-like receptor-induced signaling and activation of proinflammatory mediators. In this study, we hypothesized that if inflammation plays a key role in renal failure, then the anti-inflammatory effect of IRAK-4 inhibitor should be effective in improving CKD. To determine its pharmacological potency, we investigated the renoprotective properties of the novel IRAK-4 inhibitor AS2444697 (N-[3-carbamoyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl]-2-(2-methylpyridin-4-yl)-1,3-oxazole-4-carboxamide hydrochloride (1:1)) in 5/6 nephrectomized (Nx) rats, a model of CKD. Six weeks' repeated administration of AS2444697 (0.3-3 mg/kg, twice daily) dose-dependently and significantly reduced urinary protein excretion and prevented the development of glomerulosclerosis and interstitial fibrosis without affecting the blood pressure.