Induction of Antimicrobial Protein S100A15 Expression by Oral Microbial Pathogens Is Toll-like Receptors-Dependent Activation of c-Jun-N-Terminal Kinase (JNK), p38, and NF-κB Pathways

Abstract

The antimicrobial protein S100A15 belongs to the S100 family, which is differentially expressed in a variety of normal and pathological tissues. Although the function of S100A15 protein has been discussed in several studies, its induction and regulation in oral mucosa, so far, are largely unknown. In this study, we demonstrate that S100A15 is induced by the stimulation of oral mucosa with gram− or gram+ bacterial pathogens, as well as with the purified membrane components, namely lipopolysaccharides (LPS) and lipoteichoic acid (LTA). The stimulation of the human gingival fibroblast (GF) and the human mouth epidermal carcinoma (KB) cell lines with either gram− or gram+ bacterial pathogens or their purified membrane components (LPS and LTA) results in the activation of NF-κB, apoptosis-regulating kinase1 (ASK1), and MAP kinase signaling pathways including, c-Jun N-terminal kinase (JNK) and p38 together with their physiological substrates AP-1 and ATF-2, respectively. Inhibition of S100A15 by antibodies-mediated Toll-like receptor 4 (TLR4) or Toll-like receptor 2 (TLR2) neutralization reveals the induction of S100A15 protein by LPS/gram− bacterial pathogens to be TLR4- dependent mechanism, whereas induction by LTA/gram+ bacterial pathogens to be TLR2- dependent mechanism. Pre-treatment of GF and KB cells with JNK (SP600125), p38 (SB-203580), or NF-κB (Bay11-7082) specific inhibitors further demonstrates the importance of JNK, p38 and NF-κB pathways in the regulation of gram−/gram+ bacterial pathogen-induced S100A15 expression. Our data provide evidence that S100A15 is induced in cancer and non-cancer oral mucosa-derived cell lines by gram−/gram+ bacterial pathogens and provide insight into the molecular mechanisms by which gram− and gram+ bacterial pathogens induce S100A15 expression in the oral mucosa.

Curcumin Alleviates Osteoarthritis Through the p38MAPK Pathway: Network Pharmacological Prediction and Experimental Confirmation

“…ASK1, an apoptotic signal-regulating kinase, can be activated by stress-related stimuli to activate MEKK4 and MEKK3, leading to p38 activation and the induction of apoptosis through signals associated with the mitochondrial cell death pathway. 24 , 25 , 27 We observed elevated levels of ASK1 and MEKK3 in the SNP group; however, treatment with curcumin attenuated their expression ( Figure 5D–F ). Other studies have demonstrated that the inhibition of pkcδ expression and phosphorylation can effectively suppress the activation of the p38/MAPK signaling pathway.…”

“…On the basis of the enrichment results and previous studies, we speculated that oxidative stress, apoptosis, and the p38 mitogen-activated protein kinase (p38/MAPK) signaling pathway play important roles in the progression of OA. 24 , 25 According to the aforementioned data, the core targets were separately imported into the AutoDock Vina 1.1.2 software and docked with curcumin ( Figure 1E ). Hydrogen bonds formed between the molecules are represented by yellow dotted lines in Figure 1E , and the relevant binding energies are shown in Table 1 .…”