6.1.1. Regulation of Inflammatory Mediators.

*T. impetiginosa* can alter the expression of signaling molecules involved in the inflammation process, including nitric oxide (NO), prostaglandin (PGE2), and leukotriene B4 (LTB4) [8,15,28]. NO is essential for maintaining homeostasis and protecting human hosts and provides immunosuppressive effects as well as immunopathological and immunoprotective activities [44]. PGE2 is a mediator of inflammation, especially in diseases such as rheumatoid arthritis and osteoarthritis, playing an important role in stimulating the inflammatory response, facilitating tissue regeneration, and maintaining homeostasis [45]. LTB4, a pro-inflammatory lipid mediator, is synthesized from arachidonic acid, expressed on many inflammatory and immune cells, and is a powerful chemokine that promotes migration of macrophages and neutrophils to tissues [46]. *T. impetiginosa* can also inhibit the proinflammatory cytokines interleukin (IL)-1β and IL-6 [15,47]. IL-1β has an important homeostatic function; however, overproduction of IL-1β can result in pathophysiological changes related to pain and inflammation [48]. Likewise, IL-6 is a pro-inflammatory mediator with pleiotropic effects on immune response, inflammation, and hematopoiesis, but excessive production of IL-6 can cause various diseases [49]. In addition, the mRNA expressions of IL-1β and inflammatory genes inducible NO synthase (iNOS) and cyclooxygenase (COX)-2 were markedly decreased when treated with *T. impetiginosa* [8,15,28,47]. Information gained from in vitro and in vivo models provided insights to other researchers for further investigation. Some focused on macrophages, the main cells involved in inflammation, while others focused on neutrophils, the most abundant blood leukocytes, and their role in defense against pathogens [50,51]. Previously, Byeon et al. [8] discovered that suppression of PGE2 production negatively regulated the macrophage-mediated inflammatory response. Similarly, Suzuki et al. [52] found that *T. impetiginosa* repressed neutrophil activation. Interestingly, *T. impetiginosa* did not inhibit the migration of neutrophils but instead inhibited the reactive oxygen species (ROS) produced by migrating neutrophils. The ROS produced from normal cellular metabolism play an important role in the signaling pathways of plant and animal cells in response to environmental changes [53], and future studies should investigate their mechanisms and active substances in the context of neutrophil functional modulation.

Our body has two protective e ffects against infections in the form of innate and adaptive immune cells. Adaptive immune cells include T and B cells, while innate immune cells include macrophages, dendritic cells, and other cell types. Dendritic cells are the most e ffective antigen presenting cells due to their ability to express high levels of major histocompatibility complex II (MHC II), cluster di fferentiation 80 (CD80), and CD86 that are required for antigen presentation. This expression allows dendritic cells to e ffectively trigger an immune response [54]. Dendritic cells are predominantly found in two forms, mature and immature. Mature dendritic cells are important for stimulating the T cell immune response, while immature dendritic cells support T cell tolerance [55]. Previous research has discovered that the water extract of *T. impetiginosa* impacted dendritic cells by upregulating the expression of MHC II and CD86, the markers of dendritic cell maturation, but had no e ffect on production of pro-inflammatory cytokines. On the other hand, dendritic cells can a ffect the di fferentiation of CD4+ T cells, which are important for adaptive immunity, while treatment with *T. impetiginosa* can induce di fferentiation of CD4+ T cells, resulting in induction of Th2 and di fferentiation of regulatory T cells. The expansion of regulatory T and Th2 cells may suppress the Th1 response, thereby preventing dextran sulfate sodium (DSS)-induced colitis in mice [29].
