Antagonist of interferon-inducible protein 10/CXCL10 ameliorates the progression of autoimmune sialadenitis in MRL/lpr mice.

Abstract

OBJECTIVE:

Mononuclear cell infiltration of the salivary glands is a major feature of Sjögren's syndrome (SS) and its animal model. Local generation of chemokines and the presence of chemokine receptors on the infiltrating cells may be involved in this process. We undertook the present study to investigate the expression of chemokines during the development of autoimmune sialadenitis in MRL/lpr mice and the therapeutic effect of chemokine antagonists on sialadenitis.

METHODS:

NH2-terminal-truncated interferon-inducible protein 10 (IP-10)/CXCL10 analogs were transfected into a nonmetastatic fibroblastoid cell line, MRL/N-1, and injected subcutaneously into MRL/lpr mice, and the effects on sialadenitis were monitored.

RESULTS:

IP-10 analogs truncated by 5 or more amino acid residues from the N-terminal failed to induce chemotaxis and calcium influx by CXCR3-expressing cells. Of these, the most potent antagonist (AT) (IP-10-AT) was a molecule with methionine added after removal of the 5 N-terminal amino acid residues. Significantly increased expression of the Th1-associated chemokines IP-10, monokine induced by interferon-gamma/CXCL9, and interferon-inducible T cell chemoattractant/CXCL11 was induced in the ductal epithelium by interferon-gamma produced in the salivary glands, whereas expression of the Th2-associated chemokines thymus and activation-regulated chemokine (TARC)/CCL17 and monocyte-derived chemokine/CCL22 was almost undetectable during sialadenitis. Inoculation of IP-10-AT into MRL/lpr mice during the early stage of sialadenitis significantly reduced periductal mononuclear cell infiltration and parenchymal destruction compared with these features in control and TARC-AT-bearing mice. This was due to a significant reduction in infiltration of CXCR3+ T cells, predominantly Th1 cells, resulting in decreased interferon-gamma production.

CONCLUSION:

We prepared a novel potent IP-10 antagonist and demonstrated its ability to ameliorate the progression of autoimmune sialadenitis. This agent may provide a new therapeutic approach to SS.

• Authors: Hitoshi Hasegawa, Atsushi Inoue, Masashi Kohno, Masatake Muraoka, Tatsuhiko Miyazaki, Miho Terada, Takashi Nakayama, Osamu Yoshie, Masato Nose, Masaki Yasukawa
• Journal: Arthritis and rheumatism (Arthritis Rheum) Vol. 54 Issue 4 Pg. 1174-83 (Apr 2006) ISSN: 0004-3591 [Print] United States
• PMID: 16575871 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Chemokine CXCL10
• Chemokines
• Chemokines, CXC
• Cytokines
• Interferon-gamma

Topics

• Animals
• Autoimmune Diseases (prevention & control)
• Chemokine CXCL10
• Chemokines (biosynthesis)
• Chemokines, CXC (antagonists & inhibitors)
• Cytokines (biosynthesis)
• Disease Progression
• Interferon-gamma (antagonists & inhibitors)
• Mice
• Mice, Inbred MRL lpr
• Sialadenitis (immunology, prevention & control)
• Submandibular Gland (immunology)