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

Abstract

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.

Adipose tissue is prominent in salivary glands of Sjögren’s syndrome patients and appears to influence the microenvironment in these organs

“…In order to further characterise the SG microenvironment in relation to adipose tissue replacement, we examined the expression pattern of IL-6; a proinflammatory cytokine [45] with antiapoptotic and tissue protective functions [46][47][48]. Through immunohistochemical staining of SG biopsies, IL-6 was detected in FI rich regions in both SS patients and non-SS controls.…”

“…We hypothesise that there could be a predictive relationship between the stage of disease and adipose tissue replacement in the gland. Furthermore, it has previously been shown that adipocytes express interleukin-6 (IL-6), which is a proinflammatory cytokine [45], yet with both antiapoptotic and tissue protective functions [46][47][48]. This is why we wished to examine the expression of IL-6 in relation to fatty replacement in the SG tissue of SS patients, and further explore the SG microenvironment.…”

Serum and Ectopic Endometrium from Women with Endometriosis Modulate Macrophage M1/M2 Polarization via the Smad2/Smad3 Pathway

“…ESCs were cultured in DMEM supplemented with 10% FBS. When the cells reached approximately 80% confluence, the medium was removed and replaced with serum-free medium, with addition of 10 −8 mol/l estrogen (E 2 ), 10 −7 mol/l progestin (P), 10 −8 mol/l E 2 + 10 ng/ml recombinant IL-6 [ 18 ], 10 −7 mol/l P + 10 ng/ml IL-6, 10 −8 mol/l E 2 + 10 −7 mol/l P, or 10 −8 mol/l E 2 + 10 −7 mol/l P + 10 ng/ml IL-6 (PeproTech, Oak Park, CA, USA). The cells were cultured for 24 h, and the supernatant was collected as conditioned medium.…”

Strategy of Hepatic Metabolic Defects Induced by beclin1 Heterozygosity in Adult Zebrafish

“…On the other side, it has been reported that suppression of autophagy by PI3K/AKT activation accelerates tumor growth due to inflammation [34,35]. Interleukin-6, a family of cytokinesis, is usually associated with inflammation during carcinogenesis and has been reported to inhibit or delay apoptosis [36][37][38]. IL-6 is considered as a malevolent player that promotes tumor initiation and macrophages infiltration and is found to be closely related to STAT3 (Signal Transducers and Activators of Transcription-3) [38][39][40].…”