Amelioration of lacrimal gland inflammation by oral administration of K-13182 in Sjögren's syndrome model mice

T. Nishiyama, K. Mishima, K. Obara, H. Inoue, T. Doi, S. Kondo, M. Saka, Y. Tabunoki, Y. Hattori, T. Kodama, K. Tsubota, I. Saito

Research output: Contribution to journalArticlepeer-review

10 Citations (Scopus)

Abstract

Regulation of the adhesion of mononuclear cells to endothelial cells is considered to be a critical step for the treatment of inflammatory diseases, including autoimmune diseases. K-13182 was identified as a novel inhibitor for these adhesions. K-13182 inhibited the expression of vascular cell adhesion molecule-1 (VCAM-1, CD106) on human umbilical vein endothelial cells (HUVECs) and on mouse vascular endothelial cell line (MAECs) induced by tumour necrosis factor (TNF)-α. K-13182 also inhibited the adhesion of mononuclear cells to these HUVECs and MAECs, indicating that K-13182 suppressed these adhesions mediated by cellular adhesion molecules including VCAM-1. To evaluate the therapeutic effect in autoimmune disease model mice, K-13182 was orally administered to non-obese diabetic (NOD) mice as Sjögren's syndrome (SS) model mice. Severe destructive inflammatory lesions were observed in the lacrimal glands of vehicle-treated control mice; however, 8-week administration of K-13182 inhibited the mononuclear cell infiltration into the inflammatory lesions of the lacrimal glands. In K-13182-treated mice, the decrease in tear secretion was also prevented compared to the control mice. In addition, the apoptosis and the expression of FasL (CD178), perforin, and granzyme A was suppressed in the lacrimal glands of K-13182-treated mice. Therefore, K-13182 demonstrated the possibility of therapeutic efficacy for the inflammatory region of autoimmune disease model mice. These data reveal that VCAM-1 is a promising target molecule for the treatment of autoimmune diseases as a therapeutic strategy and that K-13182 has the potential as a new anti-inflammatory drug for SS.

Original languageEnglish
Pages (from-to)586-595
Number of pages10
JournalClinical and Experimental Immunology
Volume149
Issue number3
DOIs
Publication statusPublished - 2007 Sep

Keywords

  • Autoimmune disease
  • Endothelial cells
  • Lacrimal gland
  • NOD mouse
  • VCAM-1

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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