The salivary gland epithelial cells of patients with primary Sjögren's syndrome manifest significantly reduced responsiveness to 17β-estradiol

Abstract

Several lines of evidence indicate that salivary gland epithelial cells (SGEC) play an important role in the pathogenesis of primary Sjogren's syndrome (SS). Normal SGEC have been shown to possess functional estrogen receptors, however, the estrogenic response of SGEC in patients with SS has not been previously assessed. To address this issue, we comparatively tested cultured non-neoplastic SGEC lines from SS patients (SS-SGEC, n = 8) and from disease controls (control-SGEC, n = 12) in a standard estrogenic inhibition assay of cytokine-induced adhesion molecule expression, where the modulation of the expression of constitutive and interferon-gamma (IFNγ)-induced CD54/ICAM.1 molecules following treatment with 17β-estradiol (E2) was evaluated by flow cytometry. Similarly high ICAM.1 expression was induced by IFNγ in control-SGEC and SS-SGEC lines. E2-treatment did not modify the constitutive ICAM.1 expression in either control-SGEC or SS-SGEC lines. In line with previous results, E2-pretreatment of control-SGEC was found to impede significantly the IFNγ-induced upregulation of ICAM.1 (p = 0.003). However, such inhibition was not observed in the SS-SGEC lines (p = 0.55). Such aberrant response of SS-SGEC to estrogens did not appear to associate with altered expression of estrogen receptor (ER) proteins, as no discernible differences could be revealed by immunoblotting and immunohistochemistry in the patterns or the intensity of ERα and ERβ (ERβ1- and ERβ2-isoforms) protein expression in SGEC lines or minor salivary gland tissues between SS patients and disease controls. The deficient estrogenic responsiveness of SS-SGEC likely represents a manifestation of the intrinsic epithelial activation that characterizes SS and possibly indicates the perturbation of the immunoregulatory potential of estrogens in SS-epithelia.