A new systematic review and meta-analysis published in Medicine has highlighted the significant elevation of interleukin-18 (IL-18) in patients with primary Sjögren’s syndrome (pSS), reinforcing its role in the disease’s pathogenesis and its promise as a diagnostic and therapeutic marker.
To clarify the association between IL-18 and pSS, researchers analyzed data from 11 studies retrieved from six major databases. The analysis compared IL-18 levels in the serum and tears of pSS patients versus healthy controls. IL-18 levels were significantly elevated in individuals with pSS, with a pooled standard mean difference of 1.28. This result held when serum data were analyzed independently, suggesting a consistent upregulation of IL-18 across body fluids in affected patients. Although considerable heterogeneity was observed across the included studies (I² > 90%), the consistent trend toward elevated IL-18 levels underscored its potential as a biomarker. Moreover, the review synthesized mechanistic insights linking IL-18 to the immunopathology of pSS, further supporting its biological relevance.
IL-18, a member of the interleukin-1 superfamily, is produced by various cell types, including circulating monocytes, tissue-resident macrophages, and dendritic cells, primarily in its extracellular active form. It exerts its biological effects by binding to the IL-18 receptor (IL-18R), which is widely expressed on multiple cell types such as macrophages, monocytes, neutrophils, natural killer (NK) cells, endothelial cells, and smooth muscle cells.
IL-18, while capable of inducing Th2 cytokines independently of IL-4, is now well established as a key regulator of Th1 immune responses. Initially identified as a potent inducer of interferon-gamma (IFN-γ), IL-18 plays a central role in the differentiation and activation of Th1 cells, particularly in the presence of IL-12. Consistent with this function, the IL-18 receptor (IL-18R) is predominantly expressed on mature Th1 lymphocytes, but not on Th2 cells. Beyond its role in IFN-γ induction, IL-18 has been shown to directly stimulate the production of proinflammatory cytokines such as TNF-α and IL-1β in mature Th1 cells, macrophages, and natural killer cells. It also promotes the production of both CC and CXC chemokines, upregulates the expression of costimulatory molecules including CD40L and CD86, and contributes to tissue damage by enhancing cell-mediated cytotoxicity and driving the release of matrix metalloproteinases.
Elevated levels of IL-18 have been observed in the serum, saliva, and salivary gland tissues of patients with pSS, suggesting its role in local and systemic inflammation. IL-18 contributes to glandular damage by enhancing T-cell infiltration and IFN-γ-mediated injury to the epithelial cells of salivary and lacrimal glands. Studies have shown a positive correlation between IL-18 levels and disease activity, including autoantibody positivity (e.g., anti-Ro/SSA) and extraglandular manifestations.
The findings suggest that IL-18 not only reflects disease activity but may also play a causative role in pSS progression. As such, IL-18 could serve both as a reliable biomarker for disease monitoring and a promising target for therapeutic intervention in patients with primary Sjögren’s syndrome.
References
- Deng Y, Wang Y, Cheng Y, Lei M, Luo Y, Gu W, et al. Expression of interleukin-18 in primary Sjögren syndrome and its potential mechanisms with disease: A systematic review and meta-analysis. Medicine (Baltimore). 2025 Mar 21;104(12):e41919.
- Bombardieri M, Barone F, Pittoni V, Alessandri C, Conigliaro P, Blades MC, et al. Increased circulating levels and salivary gland expression of interleukin-18 in patients with Sjögren’s syndrome: relationship with autoantibody production and lymphoid organization of the periductal inflammatory infiltrate. Arthritis Res Ther. 2004;6(5):R447-56.