Impairment of Salivary Grands in Keratin 5/IL-18 Transgenic Mice

Objectives: Interleukin (IL)-18 is expressed in activated macrophages and also in non-immune cells, such as keratinocytes and epithelial cells. Increased levels of serum IL-18 are reported in patients with a wide variety of diseases, such as Sjögren′s syndrome (SS). Keratin 5 (K5) is mainly expressed in mucosal of skin, mouth, intestines and in thymus, salivary glands. K5/IL-18 transgenic (Tg) mice are overexpressing mature murine IL-18 using human K5 promoter. Therefore, we examined the relationship between IL-18 and SS. Methods: Wild type (WT, C57BL/6) and K5/IL-18 Tg mice were used. The mice were administered with heat- killed Propionibacterium acnes (P. acnes) injection, and LPS was injected 7 days later. Levels of IL-18 in sera and internal organs were measured 2 hours later using ELISA. For histopathological analysis, formalin-fixed samples were embedded in paraffin and stained with H&E. Mice were anesthetized with xylazine and ketamine. Pilocarpine and isoprotenenol were injected intraperitoneally to stimulate saliva production. Autoantibodies were detected by ELISA. Results: 1) IL-18 levels of K5/IL-18 Tg mice were already extremely high. Treatment of K5/IL-18 Tg mice with P. acnes and LPS induced further increase of IL-18 levels in serum, oral tissues and thymus comparable to those in WT mice. 2) We found that the histological alteration of salivary glands and thymus in K5/IL-18 Tg mice with aging, especially female mice. 3) The volume of saliva with aging in K5/IL-18 Tg mice were reduced to comparable to those in WT mice. 4) Anti-SS-A and SS-B autoantibodies in K5/IL-18 Tg mice were increased with aging. Conclusion: These results suggest that overexpressing of IL-18 with K5 promoter causes deleterious alteration in salivary glands or tissues similar to SS.