Targeting the P2X7 receptor in rheumatoid arthritis: biological rationale for P2X7 antagonism

被引：1

作者：

McInnes, I. B. ^{[1
]}

Cruwys, S. ^{[2
]}

Bowers, K. ^{[2
]}

Braddock, M. ^{[2
]}

机构：

[1] Univ Glasgow, Glasgow Biomed Res Ctr, Glasgow G12 8QQ, Lanark, Scotland

[2] AstraZeneca, Charnwood, Leics, England

来源：

CLINICAL AND EXPERIMENTAL RHEUMATOLOGY | 2014年 / 32卷 / 06期

关键词：

rheumatoid arthritis; inflammation; ion channels; P2X(7) antagonism; AZD9056; PRIMARY SJOGRENS-SYNDROME; P2X7; RECEPTOR; INFLAMMASOME; INTERLEUKIN-1; LYMPHOCYTES; CYTOKINES; CHANNELS; DISEASE; FAMILY; ATP;

D O I：

暂无

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Objective This paper aims to explore the functional significance of the P2X(7) receptor in preclinical models of rheumatoid arthritis. Methods Preclinical studies in vivo were performed using the rat streptococcal cell wall (SCW) arthritis model. Ex vivo cultures of lipopolysaccharide (LPS)/benzoylbenzoyl adenosine triphosphate (BzATP)-stimulated human monocytes were generated to test the activities of a novel, highly specific inhibitor of human P2X(7), AZD9056, on interleukin (IL)-1 and IL-18 release. Results P2X(7) receptor expression was detected in inflamed synovial tissue after onset of SCW-induced arthritis in rats. Inhibition of P2X(7) therein led to reduced articular inflammation and erosive progression. No effect was noted on acute-phase responses. Ex vivo, AZD9056 inhibited IL-1 and IL-18 release to BzATP in LPS-primed human monocytes. Conclusion P2X(7) receptor inhibition could represent a novel approach to the treatment of inflammatory arthritis. However, confirmatory clinical studies are warranted to further explore this possibility.

引用

页码：878 / 882

页数：5

共 28 条

[1] The P2X7 receptor-inflammasome complex has a role in modulating the inflammatory response in primary Sjogren's syndrome [J].

Baldini, C. ;

Rossi, C. ;

Ferro, F. ;

Santini, E. ;

Seccia, V. ;

Donati, V. ;

Solini, A. .

JOURNAL OF INTERNAL MEDICINE, 2013, 274 (05) :480-489

[2] Evidence that cytokines play a role in rheumatoid arthritis [J].

Brennan, Fionula M. ;

McInnes, Iain B. .

JOURNAL OF CLINICAL INVESTIGATION, 2008, 118 (11) :3537-3545

[3]

Caffrey M., 2004, Preparation of Benzoic Acid N- (Adamantan-1-ylmethyl) Amides as P2X7 Receptor Agonists, Patent No. [WO2004074224 A1, 2004074224]

[4] The functional network of ion channels in T lymphocytes [J].

Cahalan, Michael D. ;

Chandy, K. George .

IMMUNOLOGICAL REVIEWS, 2009, 231 :59-87

[5] Human rheumatoid synoviocytes express functional P2X7 receptors [J].

Caporali, Francesca ;

Capecchi, Pier Leopoldo ;

Gamberucci, Alessandra ;

Lazzerini, Pietro Enea ;

Pompella, Gerarda ;

Natale, Mariarita ;

Lorenzini, Sauro ;

Selvi, Enrico ;

Galeazzi, Mauro ;

Pasini, Franco Laghi .

JOURNAL OF MOLECULAR MEDICINE-JMM, 2008, 86 (08) :937-949

[6] Regulation of immune response by P2X7 receptor [J].

Chen, Lanfen ;

Brosnan, Celia F. .

CRITICAL REVIEWS IN IMMUNOLOGY, 2006, 26 (06) :499-513

[7] The pivotal role of interleukin-1 in the clinical manifestations of rheumatoid arthritis [J].

Dayer, JM .

RHEUMATOLOGY, 2003, 42 :3-10

[8] Liaisons dangereuses:: P2X7 and the inflammasome [J].

Di Virgilio, Francesco .

TRENDS IN PHARMACOLOGICAL SCIENCES, 2007, 28 (09) :465-472

[9] Immunological and Inflammatory Functions of the Interleukin-1 Family [J].

Dinarello, Charles A. .

ANNUAL REVIEW OF IMMUNOLOGY, 2009, 27 :519-550

[10] Immunodeficiency due to mutations in ORAI1 and STIM1 [J].

Feske, Stefan ;

Picard, Capucine ;

Fischer, Alain .

CLINICAL IMMUNOLOGY, 2010, 135 (02) :169-182

← 1 2 3 →