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Identification of IL-18 and Th17 Cells in Salivary Glands of Patients with Sjögren’s Syndrome, and Amplification of IL-17-Mediated Secretion of Inflammatory Cytokines from Salivary Gland Cells by IL-18¹

Azusa Sakai^*,, Yumiko Sugawara, Toshinobu Kuroishi^*, Takashi Sasano and Shunji Sugawara^2,*

^* Division of Oral Immunology, Department of Oral Biology, and Division of Oral Diagnosis, Department of Oral Medicine and Surgery, Tohoku University Graduate School of Dentistry, Sendai, Japan

IL-18 is a proinflammatory cytokine and plays an important pathogenic role in inflammatory and autoimmune disorders. IL-17 is also a proinflammatory cytokine and IL-17-secreting Th17 cells are involved in autoimmunity. However, the pathological roles of IL-18 and Th17 cells in Sjögren’s syndrome (SS) remain to be elucidated. This study showed that the expression of IL-18 was detected in acinar cells, intraducts, and CD68⁺ macrophages in salivary glands of SS patients, but not in those of healthy subjects or patients with chronic graft-vs-host disease, by immunohistochemistry, and immunoblot analysis revealed that 24-kDa precursor form of IL-18 (proIL-18) and 18-kDa mature IL-18 were detected in SS salivary glands. The majority of the infiltrating cells in the salivary glands of SS patients were CD4⁺ T cells, and CD8⁺ T cells were infiltrated to a lesser extent. The predominant expression of IL-17 was found in infiltrating CD4⁺ T cells, whereas a small number of infiltrating CD8⁺ T cells expressed IL-17. Human salivary gland HSY and acinar AZA3 cells constitutively expressed proIL-18 and caspase-1, and a calcium ionophore A23187 induced the secretion of IL-18 from the cells. HSY and AZA3 cells expressed IL-18R and IL-17R on the cell surface, and IL-18 amplified the secretion of IL-6 and IL-8 that were induced by low amounts of IL-17. Primary salivary gland cells from normal subjects partially confirmed these findings. These results suggest that IL-18 and Th17 cells detected in the salivary glands in SS patients are associated with the pathogenesis of SS in the salivary glands.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Grants-in-Aid 17390483, 17591959, and 19390461 for Scientific Research from the Japan Society for the Promotion of Science and by the 21st Century Centers of Excellence Program Special Research Grant from the Ministry of Education, Culture, Sports, Science and Technology, Japan.

² Address correspondence and reprint requests to Dr. Shunji Sugawara, Division of Oral Immunology, Department of Oral Biology Tohoku University Graduate School of Dentistry, 4-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan. E-mail address: sugawars{at}mail.tains.tohoku.ac.jp

³ Abbreviations used in this paper: SS, Sjögren’s syndrome; proIL-18, 24-kDa precursor form of IL-18; EAE, experimental autoimmune encephalomyelitis; GVHD, graft-versus-host disease.

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