Involvement of angiotensin II type 1 receptors in interleukin-1β-induced interleukin-6 production in human gingival fibroblasts

Abstract

The renin-angiotensin system is thought to be involved in inflammatory processes such as periodontitis. However, its precise role is still unclear. Therefore, in the present study the expression of the angiotensin II type 1 receptor (AT1R) was investigated in inflamed human gingival tissue, and the possible involvement of the AT1R in interleukin-1β (IL-1β)-induced interleukin-6 (IL-6) production by cultured human gingival fibroblasts (HGFs) was also studied. Immunohistochemical staining revealed that inflammatory cells and fibroblast-like cells were positive for the AT1R. However, in healthy gingival tissue, AT1R staining was very weak. The levels of AT1R mRNA and AT1R protein increased in HGFs after stimulation with IL-1β. The levels of IL-1β-induced IL6 mRNA and IL-6 protein were significantly reduced in AT1R gene-silenced HGFs compared with control HGFs. The data suggest that the AT1R may be involved in the regulation of gingival inflammation by modulating IL-1β-induced IL-6 production in HGFs.

Angiotensin II Type 1 Receptor Knockdown Impairs Interleukin‐1β‐Induced Cytokines in Human Periodontal Fibroblasts

“…In contrast to gene‐silencing results, pharmacologic pretreatment with losartan modulated only mRNA expression of IL‐6 and IL‐8 induced by IL‐1β in HPLF. To the best of the authors’ knowledge, this is the first report to show that AT1R blockade can influence HPLF mRNA expression, and these results confirm literature data reporting that use of AT1R antagonist did not significantly reduce IL‐6 levels in HGF 26 . Conversely, it is known that in vascular smooth muscle cells, antagonist of extracellular Ang II receptor (CV‐11974) did not influence intracellular effects of this peptide 44 .…”

“…Ang II has been related to AT1R translocation to nuclear compartment of neurons, 45 and nuclear localization of AT1R results in specific nuclear activation 46 . Thus, these studies suggest that Ang II and AT1R in HGFs exert their functions inside cells 26 …”

“…Some studies have shown involvement of Ang II in increase of proinflammatory cytokines, such as IL‐6, is important in periodontal pathogenesis, 24 , 25 although the exact mechanism is not completely understood. A previous study in human gingival tissue demonstrated presence of ACE, angiotensinogen, and AT1R mRNA and protein in cultured HGFs 26 . In addition, AT1R antagonist losartan was able to prevent Aggregatibacter actinomycetemcomitans– induced alveolar bone loss associated with rheumatoid arthritis in mice, 27 therefore emphasizing a possible role for RAS in development and progression of periodontal disease 28 , 29 …”

“…A previous study in human gingival tissue demonstrated presence of ACE, angiotensinogen, and AT1R mRNA and protein in cultured HGFs. 26 In addition, AT1R antagonist losartan was able to prevent Aggregatibacter actinomycetemcomitans-induced alveolar bone loss associated with rheumatoid arthritis in mice, 27 therefore emphasizing a possible role for RAS in development and progression of periodontal disease. 28,29 A recent study demonstrated that renin inhibitor aliskiren and AT1R antagonist losartan significantly blocked experimental ligature-induced periodontitis in rats.…”

Retracted: Expression of angiotensin II and its receptors in cyclosporine‐induced gingival overgrowth

“…Furthermore, it is not clear how local Ang II is produced in human gingival tissues independent of ACE activity because Ang II is usually produced from angiotensinogen in the presence of renin and ACE. Recent studies have provided evidence of lower expression of ACE in different gingival tissues, including human gingiva . In this regard, we would like to suggest the following two key molecules that contribute to ACE‐independent Ang II generation: one is mast cell‐derived chymase by which Ang II is produced from Ang I, and the other is tryptase by which Ang II is directly produced from angiotensinogen at a weakly acidic pH.…”