HM71224, a novel Bruton’s tyrosine kinase inhibitor, suppresses B cell and monocyte activation and ameliorates arthritis in a mouse model: a potential drug for rheumatoid arthritisReport as inadecuate




HM71224, a novel Bruton’s tyrosine kinase inhibitor, suppresses B cell and monocyte activation and ameliorates arthritis in a mouse model: a potential drug for rheumatoid arthritis - Download this document for free, or read online. Document in PDF available to download.

Arthritis Research and Therapy

, 18:91

First Online: 18 April 2016Received: 23 January 2016Accepted: 05 April 2016

Abstract

BackgroundBruton’s tyrosine kinase Btk is critical for activation of B cells and myeloid cells. This study aimed to characterize the effects of HM71224, a novel Btk inhibitor, both in vitro and in a mouse model of experimental arthritis.

MethodsThe kinase inhibition profile of HM71224 was analyzed. The in vitro effects of HM71224 on B cells and monocytes were analyzed by examining phosphorylation of Btk and its downstream signaling molecules, along with cytokine production and osteoclast formation. The in vivo effects of HM71224 were investigated in a mouse model of collagen-induced arthritis CIA.

ResultsHM71224 irreversibly bound to and inhibited Btk IC50 = 1.95 nM. The compound also inhibited the phosphorylation of Btk and its downstream molecules such as PLCγ2, in activated Ramos B lymphoma cells and primary human B cells in a dose-dependent manner. Furthermore, HM71224 effectively inhibited the production of tumor necrosis factor TNF-α, interleukin IL-6, and IL-1β by human monocytes, and osteoclast formation by human monocytes. Finally, HM71224 improved experimental arthritis and prevented joint destruction in a murine model of CIA.

ConclusionsHM71224 inhibits Btk in B cells and monocytes and ameliorates experimental arthritis in a mouse model. Thus, HM71224 is a potential novel therapeutic agent for rheumatoid arthritis in humans.

KeywordsB cells Btk inhibitor Inflammation HM71224 Monocytes Rheumatoid arthritis Osteoclast AbbreviationsBCRB cell receptor

BMMsmurine bone marrow-derived macrophages

BtkBruton’s tyrosine kinase

CIIbovine type II collagen

CIAcollagen-induced arthritis

EGFRepidermal growth factor receptor

ELISAenzyme-linked immunosorbent assay

ERKextracellular signal-regulated kinase

FcγRFcγ receptor

FRETfluorescence resonance energy transfer

ICsimmune complexes

ILinterleukin

IPimmunoprecipitation

JAKJanus kinase

LPSlipopolysaccharide

MAPmitogen-activated protein

micro-CTmicro-computed tomography

NF-κBnuclear factor-κB

PDCplasmacytoid dendritic cell

PLCγ2phospholipase-Cγ2

RArheumatoid arthritis

SLEsystemic lupus erythematosus

TLRtoll-like receptor

TNFtumor necrosis factor

TRAPtartrate-resistant acid phosphatase

Electronic supplementary materialThe online version of this article doi:10.1186-s13075-016-0988-z contains supplementary material, which is available to authorized users.

Jin Kyun Park and Joo-Yun Byun are two co-first authors

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Author: Jin Kyun Park - Joo-Yun Byun - Ji Ah Park - Yu-Yon Kim - Ye Ji Lee - Jeong In Oh - Sun Young Jang - Young Hoon Kim -

Source: https://link.springer.com/







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