Periodontitis is an infection of periodontal tissues which are the supportive structure for the teeth. In the complex structure of periodontal tissues, gingival epithelium is directly exposed to periodontal bacteria and their products, by receiving and transmitting signals, plays an important role in the overall dialogue that occurs between pathogens and the host. PARs are expressed and function on GECs as a part of the immuno-surveillance system. These receptors are clearly important for GECs responses to the environment that may include pathogenic or physiological products.
Four PAR family members (PAR-1, −2, −3, and −4) have been identified so far. In this study we showed that PAR-1, PAR-2 and PAR-3 are expressed in GECs, but PAR-4 is not expressed in GECs. Many researchers have already reported the expression of PARs in a wide variety of cell types, while there was controversy about the expression of PARs [
2,
3,
13,
17]. There are also some studies about the expression of PARs in GECs, but most studies were concerned on the expression and the roles of PAR-2. Overexpression of PAR-2 has been positively associated with inflammatory clinical parameters and with the levels of interleukin-6 (IL-6), IL-8, tumor necrosis factor alpha, matrix metalloprotease-2 (MMP-2), MMP-8, hepatocyte growth factor and vascular endothelial growth factor [
5,
24,
25]. Only one research found PAR-1, PAR-2 and PAR-3 expression in KB cells by RT-PCR and PAR-1, PAR-2 and PAR-3 expression in GECs by immunohistochemical studies [
17]. In our study, RT-PCR and flow cytometry were used to analyse the expression of PARs. The results were corroborated the PAR-1, PAR-2 and PAR-3 expression in GECs.
In gingival epithelium, arginine-specific cysteine proteases (Arg-gingipain, Rgp) from
P. gingivalis, a major pathogen associated with chronic periodontitis, activate PARs and induce expression of inflammatory cytokines [
22,
26,
27]. The PAR family is structurally unrelated to the pattern recognition receptor family (PRR) but, like PRRs, they signal potential danger in the environment by activating innate immune markers and inflammatory responses [
28]. However, little is known about their function when they are activated by their agonist enzymes, thrombin and trypsin or trypsin-like enzymes, in gingival epithelium. PARs are expressed by a wide variety of cell types and are suggested to play important roles in physiological processes, such as growth, development, inflammation, tissue repair and pain [
29]. Our study demonstrated that the expression of PAR-2 was upregulated with
P. gingivalis supernatant treatment compared to untreated control cells. Conversely, PAR-1 and PAR-3 expression was significantly downregulated, after
P. gingivalis supernatant treatment. In fact, PAR-2 activation has been associated with several chronic inflammatory conditions [
3,
30‐
32]. Furthermore, in vitro and in vivo studies have clearly suggested that PAR-2 also plays a role in periodontal inflammation [
15,
16,
33,
34]. PAR-1 activation, via thrombin or man-made activating peptides, has been implicated as a potential regulator of both pain and inflammation [
35‐
37]. A recent study also showed that PAR-1 was expressed in gingival tissues [
18] and PAR-1 activation by thrombin may play a role in the repair and homeostasis of periodontal tissues [
38]. The role of PAR-3 is of interest because the function of this apparently non-signaling receptor remains obscure [
9,
39,
40]. The ability of PAR-3 to generate an intracellular signal also remains in doubt because it lacks the cytoplasmic tail domain shown in other PARs, which is required to couple with G-proteins [
9]. A recent study has demonstrated that PAR-3 is a critical determinant of PAR-1 function and PAR-3 may mitigate the effects of PAR-1 in activating endothelial responses, such as vascular inflammation [
41]. PAR-3 regulates PAR1 signaling by receptor dimerization. There has been controversy over the role of PARs. In some tissues they play a proinflammatory role [
42], while in other tissues they seem to have an anti-inflammatory or protective effect [
43]. This protective function may be facilitated by the upregulation of PAR-2 and the downregulation of PAR-1 and PAR-3 gene expression in response to
P. gingivalis proteases. However, further studies are required to fully elucidate the roles of PAR-1, PAR-2, and PAR-3 in the pathogenesis of periodontitis.