1. Molecular mechanisms involved in the regulation of cytokine production by muramyl dipeptide
Mark Windheim, Philip Cohen, Christine Lang, Lorna A Plater, Mark Peggie Biochem J . 2007 Jun 1;404(2):179-90. doi: 10.1042/BJ20061704.
MDP (muramyl dipeptide), a component of peptidoglycan, interacts with NOD2 (nucleotide-binding oligomerization domain 2) stimulating the NOD2-RIP2 (receptor-interacting protein 2) complex to activate signalling pathways important for antibacterial defence. Here we demonstrate that the protein kinase activity of RIP2 has two functions, namely to limit the strength of downstream signalling and to stabilize the active enzyme. Thus pharmacological inhibition of RIP2 kinase with either SB 203580 [a p38 MAPK (mitogen-activated protein kinase) inhibitor] or the Src family kinase inhibitor PP2 induces a rapid and drastic decrease in the level of the RIP2 protein, which may explain why these RIP2 inhibitors block MDP-stimulated downstream signalling and the production of IL-1beta (interleukin-1beta) and TNFalpha (tumour necrosis factor-alpha). We also show that RIP2 induces the activation of the protein kinase TAK1 (transforming-growth-factor-beta-activated kinase-1), that a dominant-negative mutant of TAK1 inhibits RIP2-induced activation of JNK (c-Jun N-terminal kinase) and p38alpha MAPK, and that signalling downstream of NOD2 or RIP2 is reduced by the TAK1 inhibitor (5Z)-7-oxozeaenol or in TAK1-deficient cells. We also show that MDP activates ERK1 (extracellular-signal-regulated kinase 1)/ERK2 and p38alpha MAPK in human peripheral-blood mononuclear cells and that the activity of both MAPKs and TAK1 are required for MDP-induced signalling and production of IL-1beta and TNFalpha in these cells. Taken together, our results indicate that the MDP-NOD2/RIP2 and LPS (lipopolysaccharide)-TLR4 (Toll-like receptor 4) signalling pathways converge at the level of TAK1 and that many subsequent events that lead to the production of pro-inflammatory cytokines are common to both pathways.
2. Renoprotective Effects of a Novel Receptor-Interacting Protein Kinase 2 Inhibitor, AS3334034, in Uninephrectomized Adriamycin-Induced Chronic Kidney Disease Rats
Akira Nagashima, Hiroaki Tominaga, Kenichi Tokita, Kumi Sakairi, Mitsuhiro Kondo, Yusuke Wada, Hiroshi Tomiyama, Tomohisa Ishikawa J Pharmacol Exp Ther . 2020 Sep;374(3):428-437. doi: 10.1124/jpet.120.265678.
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. Inflammatory mechanisms contribute to glomerulosclerosis and tubulointerstitial fibrosis, which are hallmarks of CKD leading to end-stage renal disease. Receptor-interacting protein kinase 2 (RIP2) is largely committed to nucleotide-binding oligomerization domain signaling as a direct effector and transmits nuclear factor-κB (NF-κB)-mediated proinflammatory cytokine production. In the present study, we hypothesized that if inflammation via RIP2 and NF-κB signaling plays an important role in renal failure, then the anti-inflammatory effect of RIP2 inhibitors should be effective in improving CKD. To determine its pharmacologic potency, we investigated the renoprotective properties of the novel RIP2 inhibitor AS3334034 [7-methoxy-6-(2-methylpropane-2-sulfonyl)-N-(4-methyl-1H-pyrazol-3-yl)quinolin-4-amine] in uninephrectomized adriamycin-induced CKD rats. Six weeks' repeated administration of AS3334034 (10 mg/kg, once daily) significantly reduced urinary protein excretion and prevented the development of glomerulosclerosis and tubulointerstitial fibrosis. In addition, AS3334034 showed beneficial effects on renal function, as demonstrated by a decrease in levels of plasma creatinine and blood urea nitrogen and attenuation of a decline in creatinine clearance. Furthermore, AS3334034 significantly attenuated inflammation, renal apoptosis, and glomerular podocyte loss. These results suggest that the RIP2 inhibitor AS3334034 suppresses the progression of chronic renal failure via an anti-inflammatory effect and is therefore potentially useful in treating patients with CKD. SIGNIFICANCE STATEMENT: The receptor-interacting protein kinase 2 (RIP2) inhibitor AS3334034 suppresses the progression of chronic renal failure via an anti-inflammatory effect, suggesting that the nucleotide-binding oligomerization domain-RIP2 axis might play a crucial role in the pathogenesis of inflammatory kidney diseases. AS3334034 is expected to be potentially useful in the treatment of patients with chronic kidney disease.
3. Dual Inhibition of Rip2 and IRAK1/4 Regulates IL-1β and IL-6 in Sarcoidosis Alveolar Macrophages and Peripheral Blood Mononuclear Cells
Harvinder Talwar, Ruchi Rastogi, Lobelia Samavati, Nisar Ahmad, Jaya Talreja J Immunol . 2016 Aug 15;197(4):1368-78. doi: 10.4049/jimmunol.1600258.
Sarcoidosis is a multisystem granulomatous disease of unknown etiology that primarily affects the lungs. Our previous work indicates that activation of p38 plays a pivotal role in sarcoidosis inflammatory response. Therefore, we investigated the upstream kinase responsible for activation of p38 in sarcoidosis alveolar macrophages (AMs) and PBMCs. We identified that sustained p38 phosphorylation in sarcoidosis AMs and PBMCs is associated with active MAPK kinase 4 but not with MAPK kinase 3/6. Additionally, we found that sarcoidosis AMs exhibit a higher expression of IRAK1, IRAK-M, and receptor interacting protein 2 (Rip2). Surprisingly, ex vivo treatment of sarcoidosis AMs or PBMCs with IRAK1/4 inhibitor led to a significant increase in IL-1β mRNA expression both spontaneously and in response to TLR2 ligand. However, a combination of Rip2 and IRAK-1/4 inhibitors significantly decreased both IL-1β and IL-6 production in sarcoidosis PBMCs and moderately in AMs. Importantly, a combination of Rip2 and IRAK-1/4 inhibitors led to decreased IFN-γ and IL-6 and decreased percentage of activated CD4(+)CD25(+) cells in PBMCs. These data suggest that in sarcoidosis, both pathways, namely IRAK and Rip2, are deregulated. Targeted modulation of Rip2 and IRAK pathways may prove to be a novel treatment for sarcoidosis.
CAS No.: 2126803-41-4
