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Inflammatory caspases are critical for enhanced cell death in the target tissue of Sjögren's syndrome before disease onset
Author(s) -
Bulosan Marievic,
Pauley Kaleb M,
Yo Kyumee,
Chan Edward K L,
Katz Joseph,
Peck Ammon B,
Cha Seunghee
Publication year - 2009
Publication title -
immunology and cell biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.999
H-Index - 104
eISSN - 1440-1711
pISSN - 0818-9641
DOI - 10.1038/icb.2008.70
Subject(s) - caspase , apoptosis , programmed cell death , caspase 1 , immunology , inflammation , immune system , interleukin , nod , biology , cytokine , medicine , cancer research , endocrinology , biochemistry , diabetes mellitus
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)‐1β 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)‐γ‐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.