Regulation of apoptotic cell death by cytokines in a human salivary gland cell line: Distinct and synergistic mechanisms in apoptosis induced by tumor necrosis factor α and interferon γ

Kamachi, Makoto; Kawakami, Atsushi; Yamasaki, Satoshi; Hida, Ayumi; Nakashima, Tomoki; Nakamura, Hideki; Ida, Hiroaki; Furuyama, Masako; Nakashima, Kazuaki; Shibatomi, Kazutaka; Miyashita, Taiichiro; Migita, Kiyoshi; Eguchi, Katsumi

doi:10.1067/mlc.2002.120648

Cited by 48 publications

(39 citation statements)

References 23 publications

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“…To examine the cytoprotective effects of M3R in HSG cells, the muscarinic receptor agonist CCh was tested with respect to TNF␣/IFN␥-induced apoptosis, which was reported previously to activate apoptosis signaling in HSG cells (Kamachi et al, 2002;Kulkarni et al, 2006). Consistent with a previous report, the combined TNF␣/IFN␥ treatment reduced cell viability among HSG cells (Fig.…”

Section: Resultssupporting

confidence: 69%

“…It was reported that levels of proinflammatory cytokines, such as tumor necrosis factor ␣ (TNF␣) and interferon ␥ (IFN␥), are elevated in the affected glands in SjS (Fox et al, 1994;Kolkowski et al, 1999). Those proinflammatory cytokines can induce apoptosis of salivary gland cells through caspase 3 signaling (Kamachi et al, 2002;Kulkarni et al, 2006). In contrast, it is thought that hypofunction of fluid secretion from affected glands is caused by autoantibodies against muscarinic type 3 receptor (M3R) (Li et al, 2004;Koo et al, 2008).…”

Section: Introductionmentioning

confidence: 97%

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Muscarinic Type 3 Receptor Induces Cytoprotective Signaling in Salivary Gland Cells through Epidermal Growth Factor Receptor Transactivation

Kajiya¹,

Ichimonji²,

Min³

et al. 2012

Mol Pharmacol

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Muscarinic type 3 receptor (M3R) plays a pivotal role in the induction of glandular fluid secretions. Although M3R is often the target of autoantibodies in Sjö gren's syndrome (SjS), chemical agonists for M3R are clinically used to stimulate saliva secretion in patients with SjS. Aside from its activity in promoting glandular fluid secretion, however, it is unclear whether activation of M3R is related to other biological events in SjS. This study aimed to investigate the cytoprotective effect of chemical agonist-mediated M3R activation on apoptosis induced in human salivary gland (HSG) cells. Carbachol (CCh), a muscarinic receptor-specific agonist, abrogated tumor necrosis factor ␣/interferon ␥-induced apoptosis through pathways involving caspase 3/7, but its cytoprotective effect was decreased by a M3R antagonist, a mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (ERK) inhibitor, a phosphatidylinositol 3-kinase/Akt inhibitor, or an epidermal growth factor receptor (EGFR) inhibitor. Ligation of M3R with CCh transactivated EGFR and phosphorylated ERK and Akt, the downstream targets of EGFR. Inhibition of intracellular calcium release or protein kinase C ␦, both of which are involved in the cell signaling of M3R-mediated fluid secretion, did not affect CCh-induced ERK or Akt phosphorylation. CCh stimulated Src phosphorylation and binding to EGFR. A Src inhibitor attenuated the CCh/M3R-induced cytoprotective effect and EGFR transactivation cascades. Overall, these results indicated that CCh/M3R induced transactivation of EGFR through Src activation leading to ERK and Akt phosphorylation, which in turn suppressed caspase 3/7-mediated apoptotic signals in HSG cells. This study, for the first time, proposes that CChmediated M3R activation can promote not only fluid secretion but also survival of salivary gland cells in the inflammatory context of SjS.

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Section: Resultssupporting

confidence: 69%

Section: Introductionmentioning

confidence: 97%

Muscarinic Type 3 Receptor Induces Cytoprotective Signaling in Salivary Gland Cells through Epidermal Growth Factor Receptor Transactivation

Kajiya¹,

Ichimonji²,

Min³

et al. 2012

Mol Pharmacol

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“…Between the major proinflammatory cytokines found to be important in SS there is TNF-a. TNF-a, in combination with IFN-c, sensitizes epithelial salivary gland SS cells to apoptosis (Kamachi et al 2002;Kulkarni et al 2006), plays a role in the presentation of autoantigens as the nuclear antigens Ro, La, and alpha fodrin, recognized by autoantibodies in many SS patients (McArthur et al 2002) and high levels of TNF-a and TNF-a secreting cells have been found in peripheral blood and in lymphocytic infiltrates in salivary gland biopsies from patients with SS (Willeke et al 2003). In addition, TNF-a and its receptors are present in biopsies of healthy controls but are expressed at higher levels in SS patients (Koski et al 2001).…”

Section: Discussionmentioning

confidence: 96%

Expression of pro-inflammatory TACE-TNF-α-amphiregulin axis in Sjögren’s syndrome salivary glands

Sisto

Lisi

Lofrumento

et al. 2010

Histochem Cell Biol

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The tumor-necrosis-factor-converting-enzyme (TACE)-TNF-α-Amphiregulin (AREG) axis plays an important pathogenic role in inflammatory and autoimmune disorders. However, the pathological roles of these proteins in the chronic autoimmune disease Sjögren's syndrome (SS) remain to be elucidated. It is known that the TACE-AREG axis is clearly part of a larger cascade of signals that starts with the activation of Furin, responsible for maturation of TACE that, in turn, determines the production of active TNF-α, directly involved in the up-regulation of AREG expression. This study showed that Furin, TACE, TNF-α, and AREG proteins, detected in acinar and ductal cells of human salivary glands from SS patients, increased remarkably in comparison with biopsies of labial salivary glands from healthy controls. The changes in Furin, TACE, TNF- α, and AREG proteins' level detected in salivary glands biopsies of SS patients could be responsible for pro-inflammatory cytokines overexpression characterizing Sjögren's syndrome.

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“…Apoptosis of exocrine gland cells is one of the early pathologic events that promote the innate immune activation and lymphocyte-mediated autoimmune responses, which propel the development and onset of SS [25–29]. IFN-γ and TNF-α, two pro-inflammatory cytokines that are dramatically elevated in the salivary gland and serum of SS patients [30–32], have been shown to induce caspase-3 activation and apoptosis in salivary gland epithelial cells and disrupt the function of tight junctions [33–37]. Exocrine gland-specific transgenic expression of retinoblastoma-associated protein 48 (RbAP48) in mice results in apoptosis of the LAC and salivary gland tissues [38, 39].…”

Section: Introductionmentioning

confidence: 99%

Interleukin-6 inhibits apoptosis of exocrine gland tissues under inflammatory conditions

Zhou

Jin²,

Patel

et al. 2015

Cytokine

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Interleukin (IL)-6 is a multi-functional cytokine that can either promote or suppress tissue inflammation depending on the specific disease context. IL-6 is elevated in the exocrine glands and serum of patients with Sjögren’s syndrome (SS), but the specific role of IL-6 in the pathogenesis of this disease has not been defined. In this study, we showed that IL-6 expression levels were increased with age in C56BL/6.NOD-Aec1Aec2 mice, a primary SS model, and higher than the control C57BL/6 mice. To assess the role of IL-6 during the immunological phase of SS development, a neutralizing anti-IL-6 antibody was administered into 16 week-old female C56BL/6.NOD-Aec1Aec2 mice, 3 times weekly for a consecutive 8 weeks. Neutralization of endogenous IL-6 throughout the immunological phase of SS development led to increased apoptosis, caspase-3 activation, leukocytic infiltration, and IFN-γ- and TNF-α production in the salivary gland. To further determine the effect of IL-6 on the apoptosis of exocrine gland cells, recombinant human IL-6 or the neutralizing anti-IL-6 antibody was injected into female C57BL/6 mice that received concurrent injection of anti-CD3 antibody to induce the apoptosis of exocrine glands. Neutralization of IL-6 enhanced, whereas administration of IL-6 inhibited apoptosis and caspase-3 activation in salivary and lacrimal glands in this model. The apoptosis-suppressing effect of IL-6 was associated with up-regulation of Bcl-xL and Mcl-1 in both glands. Moreover, IL-6 treatment induced activation of STAT3 and up-regulated Bcl-xL and Mcl-1 gene expression in a human salivary gland epithelial cell line. In conclusion, IL-6 inhibits the apoptosis of exocrine gland tissues and exerts a tissue-protective effect under inflammatory conditions including SS. These findings suggest the possibility of using this property of IL-6 to preserve exocrine gland tissue integrity and function under autoimmune and inflammatory conditions.

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Regulation of apoptotic cell death by cytokines in a human salivary gland cell line: Distinct and synergistic mechanisms in apoptosis induced by tumor necrosis factor α and interferon γ

Cited by 48 publications

References 23 publications

Muscarinic Type 3 Receptor Induces Cytoprotective Signaling in Salivary Gland Cells through Epidermal Growth Factor Receptor Transactivation

Muscarinic Type 3 Receptor Induces Cytoprotective Signaling in Salivary Gland Cells through Epidermal Growth Factor Receptor Transactivation

Expression of pro-inflammatory TACE-TNF-α-amphiregulin axis in Sjögren’s syndrome salivary glands

Interleukin-6 inhibits apoptosis of exocrine gland tissues under inflammatory conditions

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