ACR Meeting Abstracts

ACR Meeting Abstracts

Abstract Number: 856

Am80, a Retinoic Acid Receptor Agonist, Ameliorates Murine Vasculitisthrough the Suppression of Neutrophil Migration and Activation

Chie Miyabe1, Yoshishige Miyabe1, Noriko Miura2, Kei Takahashi3, Yuya Terashima4, Etsuko Toda4, Fumiko Honda5, Tomohiro Morio5, Naohito Ohno2, Jun-ichi Suzuki6, Mitsuaki Isobe7, Kouji Matsushima4, Ryoji Tsuboi8, Nobuyuki Miyasaka1 and Toshihiro Nanki9, 1Department of Medicine and Rheumatology, Tokyo Medical and Dental University, Tokyo, Japan, 2Laboratory for Immunopharmacology of Microbial Products, School of Pharmacy, Tokyo University of Pharmacy and Life Science, Tokyo, Japan, 3Department of Pathology, Toho University Ohashi Medical Center, Tokyo, Japan, 4Department of Molecular Preventive Medicine, The University of Tokyo, Tokyo, Japan, 5Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo, Japan, 6Department of Advanced Clinical Science and Therapeutics, The University of Tokyo, Tokyo, Japan, 7Department of Cardiovascular Medicine, Tokyo Medical and Dental University, Tokyo, Japan, 8Department of Dermatology, Tokyo Medical University, Tokyo, Japan, 9Department of Rheumatology, Tokyo Medical and Dental University, Tokyo, Japan

Meeting: 2012 ACR/ARHP Annual Meeting

Keywords: ,

Session Information

Title: Vasculitis: Pathogenesis

Session Type: Abstract Submissions (ACR)

Background/Purpose: Vasculitis is characterized by leukocyte infiltration in the vessel walls with destructive damage to mural structures. Retinoids are compounds that bind to retinoic acid receptors (RARs)and have biological activities of vitamin A, including modulatory effects on cell proliferation and differentiation. Synthetic retinoid, Am80, is a specific ligand for RAR-α/β but not RAR-γand is characterized by higher stability, fewer potential adverse effects, and superior bioavailability compared with all-trans retinoic acid. Previously we showed that Am80 ameliorated murine collagen-induced arthritis and experimental autoimmunemyositis. In this study, we examined the therapeutic effects of Am80 on a murine model of vasculitis induced by Candida albicans water-soluble fraction (CAWS).

Methods: Vasculitis was induced in BALB/c mice by intraperitoneal injection of CAWS from day 1 for 5 days. Neutrophils were depleted by injection of anti-neutrophil serum. Am80 was administrated orally once dailyfrom day 1 for 5 weeks or from day 8 for 4 weeks. Vasculitis was histologically evaluated. Number of migrated cells of labeled-adaptively transfer cells was counted. Chemotaxis was analyzed using cell mobility analysis device. Production of reactive oxygen species (ROS) and phosphorylation of mitogen-activated protein kinases was measured by flow cytometry. Concentrations of elastase, CCL2 and IL-6 were measured by enzyme-linked immunosorbent assays.

Results: Administration of CAWS induced vasculitis in the coronary arteries and aortic root with abundant neutrophil infiltration. Depletion of neutrophils reduced CAWS-induced vasculitis. Treatment with Am80 from day 1 significantly attenuated the experimental vasculitis. In addition, administration of Am80 from day 8, after the onset of vasculitis, also ameliorated the vasculitis. Am80 inhibited migration of transferred neutrophils into the site of vasculitis. In vitro, Am80 suppressed N-formyl-methionyl-leucyl-phenylalanine (fMLP)-induced chemotaxis of human peripheral blood neutrophils. Am80 reduced ROS production by phorbol 12-myristate 13-acetate, Pam3CSK4 or lipopolysaccharide (LPS)-stimulated peripheral blood neutrophils. Elastase release by fMLP and cytochalasin B-stimulated neutrophils was inhibited by incubation with Am80. Am80 also inhibited phosphorylation of extracellular signal-regulated kinase 1/2 and p38 in neutrophils-stimulated with fMLP and LPS. Moreover, Am80 reduced CCL2 and IL-6 production from human umbilical vein endothelial cells-stimulated with TNF-α or IL-1β.

Conclusion: Am80 significantly suppressed CAWS-induced vasculitis presumably through inhibition of neutrophil migration and activation.

Disclosure:

C. Miyabe,
None;

Y. Miyabe,
None;

N. Miura,
None;

K. Takahashi,
None;

Y. Terashima,
None;

E. Toda,
None;

F. Honda,
None;

T. Morio,
None;

N. Ohno,
None;

J. I. Suzuki,
None;

M. Isobe,
None;

K. Matsushima,
None;

R. Tsuboi,
None;

N. Miyasaka,
None;

T. Nanki,
None.

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