Low salivary dehydroepiandrosterone and androgen‐regulated cysteine‐rich secretory protein 3 levels in Sjögren's syndrome

Abstract

Objective. Sjögren's syndrome (SS), an autoimmune disease of exocrine glands, typically starts at the time of adrenopause. We undertook this study to test the hypothesis that SS is characterized by an insufficient androgen effect at the target tissue level.Methods. We searched for androgen response elements (AREs) in the cysteine-rich secretory protein 3 (crisp-3) gene. Dehydroepiandrosterone (DHEA) responsiveness was experimentally studied using quantitative reverse transcriptase-polymerase chain reaction and immunofluorescence staining of human submandibular gland-derived acinar cells and labial salivary gland explants with or without DHEA. Finally, glandular and salivary CRISP-3 in healthy controls and SS patients was analyzed using immunohistochemistry, in situ hybridization, and enzyme-linked immunosorbent assay. Serum DHEA sulfate (DHEAS) and salivary DHEA levels were measured using a radioimmunometric method.Results. Literature analysis and a search for AREs in gene banks suggested androgen dependency of human CRISP-3, and this was verified by studies of human submandibular gland acinar cells cultured with or without DHEA, in which DHEA increased CRISP-3 messenger RNA (mRNA) levels (P ‫؍‬ 0.018). This finding was confirmed by the results of DHEA stimulation of labial salivary gland explants. Glandular CRISP-3 mRNA and protein labeling was weak and diffuse, coupled with low secretion in saliva (mean ؎ SEM 21.1 ؎ 2.7 g CRISP-3/15 minutes in SS patients versus 97.6 ؎ 12.0 g CRISP-3/15 minutes in healthy controls; P < 0.0001). Compared with healthy controls, SS patients had low serum levels of DHEAS (P ‫؍‬ 0.008) and also low salivary levels of DHEA (mean ؎ SEM 224 ؎ 33 pmoles versus 419 ؎ 98 pmoles; P ‫؍‬ 0.005).Conclusion. CRISP-3 pathology was seen in acini remote from lymphocyte foci and is apparently not secondary to local inflammation, but may represent some systemic effect in SS. Indeed, androgen deprivation in the salivary glands of SS patients is evidenced both by low salivary levels of DHEA and by low levels of DHEA-regulated CRISP-3. This may explain some of the characteristic features of SS.

Cobra CRISP Functions as an Inflammatory Modulator via a Novel Zn2+- and Heparan Sulfate-dependent Transcriptional Regulation of Endothelial Cell Adhesion Molecules

“…CRISP-3 is up-regulated in a number of pathologies including prostate cancer (59,60), chronic pancreatitis (61), Sjögren's syndrome (62), and ectopic pregnancy (63). The present study demonstrated for the first time that natrin from the venoms of N. atra induces proinflammatory responses of ECs by inducing their adhesion molecule expression and, hence, monocytic cell adhesion.…”

Cysteine‐rich secretory proteins are not exclusively expressed in the male reproductive tract

“…Given the compelling data that CRISPs are ion channel regulators via their CRISP domains , these data raise the likely possibility that CRISPs regulate multiple aspects of mammalian physiology in the normal healthy state. Similarly, and as supported by several human EST and transcript profile experiments, the up-regulation of CRISPs in cases of disease indicate a role in pathogenesis (Tapinos et al, 2002;Liao et al, 2003;Bjartell et al, 2006;Laine et al, 2007).…”

“…Crisp3 was initially identified in the mouse salivary gland (Haendler et al, 1993) and later in the human as SGP28 (Kjeldsen et al, 1996). Subsequently, it was identified in human prostate (Kratzschmar et al, 1996) where it appears promising as a marker of prostate cancer (Kosari et al, 2002;Bjartell et al, 2006Bjartell et al, , 2007 and in the salivary glands where it appears promising as a marker for Sjögren's syndrome (Tapinos et al, 2002;Laine et al, 2007). The mechanism by which CRISP3 is involved in these pathological processes is currently unknown.…”

Sjögren’s syndome and extragonadal sex steroid formation: A clue to a better disease control?

“…Secretion of CRISP-3 to saliva is also low in SS compared to healthy controls (21.1 AE 2.7 mg CRISP/15 min vs 97.6 AE 12.0 mg CRIPS/15 min, p = 0.008). It was also in this study shown that patients with SS had low salivary DHEA-S values compared to healthy controls (224 AE 33 pmol vs 419 AE 98 pmol, p = 0.005) and that DHEA increased CRISP-3 in labial salivary gland explants and also in cultured human acinar cells (p = 0.018) [13]. This strongly implies that the endocrine adrenal glandintracrine exocrine gland axis fails in SS.…”