Bulosan Marievic, Pauley Kaleb M, Yo Kyumee, Chan Edward K L, Katz Joseph, Peck Ammon B, Cha Seunghee
Department of Oral and Maxillofacial Surgery and Diagnostic Sciences (OMSDS), University of Florida College of Dentistry (UFCD), Gainesville, FL , USA.
Immunol Cell Biol. 2009 Jan;87(1):81-90. doi: 10.1038/icb.2008.70. Epub 2008 Oct 21.
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)-1beta 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)-gamma-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.
迄今为止，对于干燥综合征（SjS）中外分泌腺为何会受到免疫细胞浸润，人们知之甚少。对易患SjS的C57BL/6.NOD-Aec1Aec2小鼠的研究表明，在疾病发作前8周，下颌下腺（SMX）的腺体内稳态发生了改变，并提示炎性半胱天冬酶（半胱天冬酶-11和-1）可能参与其中。为了确定炎性半胱天冬酶在类SjS疾病发作前上皮细胞死亡增加过程中是否起关键作用，我们研究了涉及半胱天冬酶-11/半胱天冬酶-1轴的分子事件。我们的结果显示，在8周龄的C57BL/6.NOD-Aec1Aec2小鼠的SMX中，巨噬细胞中的半胱天冬酶-11、STAT-1活性、半胱天冬酶-1活性和凋亡上皮细胞同时上调。半胱天冬酶-1是白细胞介素（IL）-1β和IL-18分泌的关键因子，它导致唾液中IL-18水平升高。有趣的是，C57BL/6.NOD-Aec1Aec2小鼠SMX中的TUNEL阳性细胞与半胱天冬酶-11没有共定位，这表明半胱天冬酶-11以非细胞自主方式发挥作用。人唾液腺（HSG）细胞系凋亡增加仅发生在存在脂多糖（LPS）和干扰素（IFN）-γ刺激的人单核细胞THP-1细胞的情况下，当THP-1细胞中的半胱天冬酶-1被小干扰RNA靶向时，这种情况会逆转。综上所述，我们的研究发现，炎性半胱天冬酶对于在疾病发作前促进SjS靶组织中的促炎微环境和影响上皮细胞死亡增加至关重要。
