Modulation of Apoptosis by Cytotoxic Mediators and Cell-Survival Molecules in Sjögren's Syndrome

Abstract

The pathogenesis of Sjögren's syndrome (SS) involves multiple factors including genetic background, cell death, and exocrine dysfunction. We here discuss apoptotic control in exocrine glands in SS by showing various pro- and anti-apoptotic pathways. Although the membrane-bound and soluble form of the Fas/Fas ligand system is a leading player with activation of the death domain and caspase 8/3 cleavage, the role of soluble Fas/FasL (including its polymorphism) in apoptosis is controversial. The tumor necrosis factor related apoptosis-inducing ligand (TRAIL)-mediated apoptosis of salivary gland epithelial cells (SGECs) involves a mitochondrial pathway that includes caspase 9 cleavage. The involvement of innate immunity cells such as toll-like receptors (TLRs) has been investigated; TLR2-4 and TLR7-9 are associated with the induction of inflammation in exocrine glands of SS patients. TLR3 has the potential to induce the apoptosis of SS patients' SGECs. Linkage of epidermal growth factor (EGF) was shown in exocrine glands in SS, and it inhibited the Fas/FasL system with the help of cell-survival factors. TLR3 has dual actions to cause inflammation as well as apoptosis, which are inhibited by EGF. In conclusion, apoptosis in exocrine glands of SS patients is tightly controlled by balance of pro-apoptotic signals and growth factor.

Keywords: EGF; Fas; Sjögren’s syndrome; TLR; apoptosis; cell survival molecule; salivary gland epithelial cells.

Figure 1

Schematic overview of apoptotic control in Sjögren’s syndrome (SS). With respect to apoptosis in SS, aging, gender, genetic factors and environmental factors have been considered. As pro-apoptotic factors, the following are effectors to induce apoptosis in epithelial cells: the joining of membranous Fas (mFas) that expresses on epithelial cells and Fas ligand (mFasL) expressed on infiltrating CD4⁺T lymphocytes; cytotoxic granules such as granzyme B/Perforin in CD8⁺T cells that are adjacent to epithelial cells; TRAIL and the stimulation of toll-like receptor3 (TLR3). Even though TLR3 has the potential to induce apoptosis, TLR3 and TLR7–9 mediate inflammation in response to microbial infection. In contrast, the soluble form of FasL (sFasL) is presumed to inhibit mFas-mediated apoptosis, in which some modifications with respect to the promotor polymorphism of the soluble form of Fas/FasL might be associated with their function in apoptotic regulation.

Figure 2

Inhibition of apoptosis mediated by mFas and TRAIL. The pathway for the induction of mFas-mediated apoptosis consists of death-inducing signaling complex (DISC) formation followed by the assembly of Fas-associated protein with death domain (FADD), and the cleavage of caspases 8 and 3. One of the inhibitory mechanisms of Fas-mediated apoptosis is mediated by epidermal growth factor (EGF) and a downstream PI3K/Akt and NF-κB pathway including the expression of X-chromosome-linked inhibitor of apoptosis (XIAP). Another candidate is sFasL, which is shown to inhibit mFas-mediated apoptosis by combining with mFas. Although pro-apoptotic pathway in SS is similar to general apoptotic pathway, EGF-mediated inhibition of apoptosis might be specific in SS. TNF-related apoptosis-inducing ligand (TRAIL) rapidly induces the apoptosis of cultured salivary gland epithelial cells (SGECs), in which a mitochondrial pathway that includes a release of cytochrome C, the cleavage of caspase 9, and the activation of Apaf-1 after the truncation of Bid is also involved. Bcl-2 family molecules such as Bcl-2 and Bcl-xL are considered to inhibit this mitochondrial pathway by inhibiting cytochrome C release.

Figure 3

Role of TLR3, 7 and 9 in SS. Toll-like receptor3 (TLR3), which responds to double-strand RNA (dsRNA) of microbes, usually activates the NF-κB pathway and interferon regulatory factor (IRF) 3–7 downstream of Toll-IL-1 receptor domain-containing adaptor inducing IFN-β (TRIF). However, TLR3 also has the ability to induce apoptosis of SGECs by activating a RIP pathway that includes the assembly of FADD and the cleavage of caspase 3. Epidermal growth factor (EGF) and EGF-mediated heme oxygenase (HO)-2 and heat shock protein (HSP)-27 are candidates for the inhibition of TLR3-mediated apoptosis. Crucial roles are also played by TLR7 and TLR9 signaling, which respond to single-strand RNA (ssRNA) and to the CpG DNA of viruses in plasmatoid dendritic cells in exocrine glands in SS, myeloid differentiation factor (MyD) 88, and its downstream pathways including the NF-κB pathway and the phosphorylation of IRF7. NF-κB and IRF7 mediate the up-regulation of inflammatory cytokines and type I interferon (IFN) including IFN-α and IFN-β. Investigations into the detailed functions of TLR7–9 signaling in epithelial cells of patients with SS are in progress.