1. ¹Department of Oral and Maxillofacial Surgery and Diagnostic Sciences (OMSDS), University of Florida College of Dentistry (UFCD), Gainesville, FL, USA
2. ²Department of Oral Biology, University of Florida College of Dentistry (UFCD), Gainesville, FL, USA
3. ³Department of Pathology, University of Florida College of Dentistry (UFCD), Gainesville, FL, USA

Correspondence: Dr S Cha, Department of Oral Surgery and Diagnostic Sciences, College of Dentistry, University of Florida, PO Box 100416, Gainesville, FL 32610, USA. E-mail: scha@dental.ufl.edu

⁴These authors contributed equally to this work.

Received 21 February 2008; Revised 30 June 2008; Accepted 15 August 2008; Published online 21 October 2008.

Abstract

To date, little is known about why exocrine glands are subject to immune cell infiltrations in Sjögren's syndrome (SjS). Studies with SjS-prone C57BL/6.NOD-Aec1Aec2 mice showed altered glandular homeostasis in the submandibular glands (SMX) at 8 weeks before disease onset and suggested the potential involvement of inflammatory caspases (caspase-11 and -1). To determine whether inflammatory caspases are critical for the increased epithelial cell death before SjS-like disease, we investigated molecular events involving caspase-11/caspase-1 axis. Our results revealed concurrent upregulation of caspase-11 in macrophages, STAT-1 activity, caspase-1 activity and apoptotic epithelial cells in the SMX of C57BL/6.NOD-Aec1Aec2 at 8 weeks. Caspase-1, a critical factor for interleukin (IL)-1 and IL-18 secretion, resulted in an elevated level of IL-18 in saliva. Interestingly, TUNEL-positive cells in the SMX of C57BL/6.NOD-Aec1Aec2 were not colocalized with caspase-11, indicating that caspase-11 functions in a noncell autonomous manner. Increased apoptosis of a human salivary gland (HSG) cell line occurred only in the presence of lipopolysaccharide (LPS-) and interferon (IFN)--stimulated human monocytic THP-1 cells, which was reversed when caspase-1 in THP-1 cells was targeted by siRNA. Taken together, our study discovered that inflammatory caspases are essential in promoting a pro-inflammatory microenvironment and influencing increased epithelial cell death in the target tissues of SjS before disease onset.