TAK1 inhibitor, (5Z)-7-Oxozeaenol inhibited expression level of pim-1 in LPS-mediated inflammatory signal pathway. In addition, kinase domain of Pim-1 play an important role in interaction with TAK1.
Pim-1 siRNA inhibited LPS-induced phosphorylation of JAK1 and STAT3 in THP-1 cells. These result suggested that Pim-1 is closely related to the JAK/STAT pathway to regulate its expression and function. Next, using KMU-11342, which has a novel Pim kinase inhibitor effect, its potential as an RA therapeutic drug and its anti-inflammatory mechanism were confirmed. Taken together, I identified anti-inflammatory effect of KMU-11342 via inhibiting of TLR4/NF-κB/NLRP3 inflammasome signaling in LPS-treated RA-FLS and THP-1 cells. In addition, it was confirmed that the differentiation of osteoclasts was also suppressed by KMU-11342. In this study, KMU-11342 inhibited multinucleated cell differentiation representing osteoclast differentiation and showed an effect of inhibiting the formation of F-actin rings. Additionally, it was shown that KMU-11342 inhibited both Cathepsin K, TRAP, NFATc-1, c-Fos, OSCAR, which are specific indicators of osteoclast. KMU-11342, inhibition of RANKL induced TAK1/MAPKs/NF-κB signal pathway in osteoclast differentiation.
As a result of this study, KMU-11342 has the potential to be developed as a therapeutic drug for RA through inhibition of inflammation and osteoclastogenesis.
Reference
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Pim-1 Regulates NLRP3 Inflammasome-mediated Inflammatory Signals
Baek, Hye Suk Department of Immunology
Graduate School Keimyung University (Supervised by Professor Kim, Shin)
(Abstract)
Pim-1 is a proto-oncogene that encodes for the serine-threonine protein kinase family. Recent studies have suggested that Pim-1 kinase
plays an important role in inflammatory signaling. However, the underlying regulatory mechanism remains unclear. In this study, I
investigated the regulatory mechanism of Pim-1 on inflammation, and the anti-inflammatory effect of a novel protein kinase inhibitor,
KMU-11342. PIM-1 knockdown suppressed lipopolysaccharide (LPS)-induced up-regulation of pro-inflammatory cytokines, inducible nitric oxide synthase
(iNOS), cyclooxygenase-2 (COX-2), phospho-Janus kinase, phospho-signal transducer and activator of transcription 3, phospho-extracellular signal-regulated
kinase, phospho-c-Jun N-terminal kinase, phospho-p38, phospho-nuclear factor
kappa B p65 (p-NF-κB p65), nuclear translocation of NF-κB p65, and
phospho-inhibitor of NF-κB kinase α/β (p-IKKα/β). PIM-1 knockdown inhibited up-regulation of Nod-like receptor family pyrin domain
containing 3 (NLRP3) and cleavage of caspase-1 induced by combination of LPS and adenosine triphosphate (ATP). Additionally, phospho-transforming
growth factor-β-activated kinase 1 (TAK1) was found to be associated with Pim-1 binding. KMU-11342 inhibited LPS-induced up-regulation of
chemokines in human rheumatoid arthritis fibroblast-like synoviocyte (RA-FLS). KMU-11342 suppressed LPS-induced up-regulation of
pro-inflammatory cytokines, iNOS, COX-2, p-IKKα/β, p-NF-κB p65, and nuclear translocation of NF-κB p65 in both RA-FLS and THP-1
cells. It suppressed up-regulation of NLRP3 and co-treatment with LPS and ATP-induced caspase-1 cleavage. KMU-11342 also inhibited receptor
activator of NF-κB-induced osteoblast differentiation and up-regulation of nuclear factor of activated T-cells, cytoplasmic 1 and c-Fos in
RAW264.7 cells. Taken together, these findings indicated that Pim-1 plays an important role in inflammatory signaling and KMU-11342 is a
promising anti-inflammatory agent.
Pim-1의 NLRP3 Inflammasome 매개 염증 신호 조절
백 혜 숙 계명대학교 대학원 의학과 면역학 전공
(지도교수 김 신)
(초록)
Pim-1은 세린-트레오닌 단백질 키나아제 family 계열의 암호화된
proto-oncogene이다. 최근 연구에 따르면 Pim-1 키나아제가 염증 신호에 중요한 역할을 한다. 그러나, 조절 메커니즘은 아직 명확하게 설명되지 않
았다. 본 연구에서는, Pim-1의 염증에서의 조절기전과 새로운 단백질 키나 아제 억제제인, KMU-11342의 항염증 효과를 조사했다. Pim-1의 억제는
LPS로 유도된 염증성 사이토카인, 유도성 일산화질소 합성효소(iNOS), 사 이클로옥시게나제-2 (COX-2), p-JAK, p-STAT, p-ERK, p-JNK, p-p38,
NF-κB p65 인산화 및 핵전사의 상향 조절을 억제하였다.
Pim-1의 억제는 LPS와 ATP의 결합에 의해 유도된 NLRP3의 상향조절과
Caspase-1의 활성을 억제했다. 게다가, TAK1은 Pim-1의 결합과 관련이 있는 것으로 밝혀졌다. KMU-11342는 류마티스 관절염 환자의 섬유아세포
유사 활막세포(RA-FLS)에서 LPS로 유도된 케모카인의 상향 조절을 억제
하였다. KMU-11342는 RA-FLS 와 THP-1 세포 모두에서 LPS 유도 염증
성 사이토카인, iNOS, COX-2, p-IKKα/β, p-NF-κB p65, NF-κB P65의 핵전이를 억제하였다. 또한 LPS와 ATP 유도 NLRP3 inflammasome을 상
향 조절과 Caspase-1의 활성을 억제했다. KMU-11342는 RAW264.7 세포 에서 RANKL 유도 파골세포 분화와 NFATc-1 및 c-Fos의 상향 조절을
억제하였다. 결과적으로, 이러한 연구 결과는 Pim-1이 염증 신호 전달에 중요한 역할을 하며, KMU-11342는 잠재적인 항염증제임을 시사한다.
□ 논문 저자 약력
1980년 대구 출생
계명대학교 식품가공학과 졸업
대구가톨릭대학교 대학원 의학과 석사
□ 논문 및 저서
「KMU-1170, a Novel Multi-Protein Kinase Inhibitor, Suppresses Infla-mmatory Signal Transduction in THP-1 Cells and Human Osteoarthritic Fibroblast-Like Synoviocytes by Suppressing Activation of NF-κB and NLRP3 Inflammasome Signaling Pathway」 Int. J. Mol Sci 2021. 1
「Anti-Inflammatory Effects of the Novel PIM Kinase Inhibitor KMU-470 in RAW 264. 7 Cells through the TLR4-NF-κB-NLRP3 Pathway」
Int. J. Mol. Sci 2020. 6
「Effect of Methanol Extract from Cassia mimosoides var. nomame on Ischemia /Reperfusion-induced Renal Injury in Rats.」 Kor. J. Herbology. 2013. 11
「Hot Water Extract of Triticum aestivum L.(Common Wheat) Ameliorates Renal Injury by Inhibiting Apoptosis in a Rat Model of Ischemia/
Reperfusio」kor. J. Herbology 2013. 5
「Synthesis and Biological Evaluation of a Novel 177Lu-DOTA-[Gly3-Cyclized (Dap4, D-Phe7, Asp10)-Arg11] a-MSH3–13 Analogue for Melanocortin-1 Receptor-Positive Tumor Targeting」Cancer Biother Radiopharm 2012. 8
「Methanol Extract of Goat’s-beard (Aruncus dioicus) Reduces Renal Injury by Inhibiting Apoptosis in a Rat Model of Ischemia-Reperfusion」