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, Kazuo Tsubota, I. Saito

Research output: Contribution to journalArticle

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

Fingerprint

Lacrimal Apparatus
Oral Administration
Inflammation
Vascular Cell Adhesion Molecule-1
Autoimmune Diseases
Human Umbilical Vein Endothelial Cells
Cell Adhesion
Endothelial Cells
Granzymes
Perforin
Inbred NOD Mouse
Therapeutic Uses
Therapeutics
Tears
Anti-Inflammatory Agents
Tumor Necrosis Factor-alpha
Apoptosis
Cell Line

Keywords

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

ASJC Scopus subject areas

  • Immunology

Cite this

Amelioration of lacrimal gland inflammation by oral administration of K-13182 in Sjögren's syndrome model mice. / Nishiyama, T.; Mishima, K.; Obara, K.; Inoue, H.; Doi, T.; Kondo, S.; Saka, M.; Tabunoki, Y.; Hattori, Y.; Kodama, T.; Tsubota, Kazuo; Saito, I.

In: Clinical and Experimental Immunology, Vol. 149, No. 3, 09.2007, p. 586-595.

Research output: Contribution to journalArticle

Nishiyama, T, Mishima, K, Obara, K, Inoue, H, Doi, T, Kondo, S, Saka, M, Tabunoki, Y, Hattori, Y, Kodama, T, Tsubota, K & Saito, I 2007, 'Amelioration of lacrimal gland inflammation by oral administration of K-13182 in Sjögren's syndrome model mice', Clinical and Experimental Immunology, vol. 149, no. 3, pp. 586-595. https://doi.org/10.1111/j.1365-2249.2007.03448.x
Nishiyama, T. ; Mishima, K. ; Obara, K. ; Inoue, H. ; Doi, T. ; Kondo, S. ; Saka, M. ; Tabunoki, Y. ; Hattori, Y. ; Kodama, T. ; Tsubota, Kazuo ; Saito, I. / Amelioration of lacrimal gland inflammation by oral administration of K-13182 in Sjögren's syndrome model mice. In: Clinical and Experimental Immunology. 2007 ; Vol. 149, No. 3. pp. 586-595.
@article{a2da8b43982e453d81fe6f8417234bf2,
title = "Amelioration of lacrimal gland inflammation by oral administration of K-13182 in Sj{\"o}gren's syndrome model mice",
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 Sj{\"o}gren'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.",
keywords = "Autoimmune disease, Endothelial cells, Lacrimal gland, NOD mouse, VCAM-1",
author = "T. Nishiyama and K. Mishima and K. Obara and H. Inoue and T. Doi and S. Kondo and M. Saka and Y. Tabunoki and Y. Hattori and T. Kodama and Kazuo Tsubota and I. Saito",
year = "2007",
month = "9",
doi = "10.1111/j.1365-2249.2007.03448.x",
language = "English",
volume = "149",
pages = "586--595",
journal = "Clinical and Experimental Immunology",
issn = "0009-9104",
publisher = "Wiley-Blackwell",
number = "3",

}

TY - JOUR

T1 - Amelioration of lacrimal gland inflammation by oral administration of K-13182 in Sjögren's syndrome model mice

AU - Nishiyama, T.

AU - Mishima, K.

AU - Obara, K.

AU - Inoue, H.

AU - Doi, T.

AU - Kondo, S.

AU - Saka, M.

AU - Tabunoki, Y.

AU - Hattori, Y.

AU - Kodama, T.

AU - Tsubota, Kazuo

AU - Saito, I.

PY - 2007/9

Y1 - 2007/9

N2 - 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.

AB - 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.

KW - Autoimmune disease

KW - Endothelial cells

KW - Lacrimal gland

KW - NOD mouse

KW - VCAM-1

UR - http://www.scopus.com/inward/record.url?scp=34547901768&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=34547901768&partnerID=8YFLogxK

U2 - 10.1111/j.1365-2249.2007.03448.x

DO - 10.1111/j.1365-2249.2007.03448.x

M3 - Article

C2 - 17614971

AN - SCOPUS:34547901768

VL - 149

SP - 586

EP - 595

JO - Clinical and Experimental Immunology

JF - Clinical and Experimental Immunology

SN - 0009-9104

IS - 3

ER -