**4. IL-23**

IL-23, consisting of a heterodimeric protein that contains subunits p19 and p40, was first cloned in 2000 [34]. IL-23 is produced by antigen-presenting cells (APCs) such as dendric cells (DCs), monocytes, and macrophages. Although IL-23 and IL-12 share subunit p40, only IL-12 can induce IFN-γ-producing Th1 cells. The increased production of IL-17 in response to IL-23 by CD4+ T cells was reported [35], and the novel population of IL-17-producing CD4+ T cells (Th17), clearly distinct from Th1 and Th2 cells, was identified in 2005 [36]. This discovery of the IL-23/Th17 pathway led to the clarification of the pathogenesis of autoimmune and autoinflammatory diseases that cannot be adequately explained by the Th1–Th2 concept [37]. Experimental evidence has demonstrated that the pathological activation of IL-23 and IL-17 triggers chronic inflammatory diseases, including SpA [38–41].

#### *IL-23 in SpA Patients*

The upregulated presence of IL-23 in SpA patients confirms the involvement of the IL-23/IL-17 pathway. In AS, the elevated serum level of IL-17 and the expression of IL-23 p19 in peripheral blood mononuclear cells were demonstrated [42,43]. Additionally, increased expression of IL-23 in regional skin in patients with Ps and in synovial tissue in patients with PsA has been reported [44,45]. Despite the elevation of IL-23 levels in the synovial fluid in rheumatoid arthritis (RA) and PsA patients, only the disease activity parameters in RA patients correlated with IL-23 expression. These results suggest the existence of a different immunoregulation process for SpA and RA [46].

One question that arises here is where IL-23 originates. Two studies have reported the involvement of the intestine. Ciccia et al. found the upregulation of IL-23 expression, but not IL-17, in the terminal ileum in patients with AS and identified resident Paneth cells as a pivotal source of IL-23 production [47]. Furthermore, they found IL-23-responsive type 3 innate lymphoid cells (ILC3) in the gut and that IL-17+ ILC3 derived from the gut is expanded in the peripheral blood. These studies suggest that the intestine is at least one of the main producers of IL-23 [48].

#### **5. IL-17**

IL-17 is a pro-inflammatory cytokine that was first identified in 1993 [49]. The IL-17 cytokine family consists of six members, from IL-17A to IL-17F. IL-17A is the prototypical member, and IL-17A and IL-17F have the highest homology and overlap in many functions. There are five members of the IL-17 receptor family: IL17-RA, IL-17RB, IL-17RC, IL17-RD, and IL-17RE. IL-17 receptors exist as heterodimers, and IL-17RA is a common subunit. The IL-17 RA and IL-17RC heterodimer is the receptor of IL-17A, IL-17F, and the heterodimer of IL-17A and IL-17F. IL-17RA is ubiquitously expressed, whereas IL-17RC is mainly expressed on non-hematopoietic cells [50].

IL-17 plays an important role in acute inflammation by accumulating neutrophils through IL-6 [37]. IL-17R knockout mice displayed a significant delay in neutrophil recruitment and an attenuated host defense against bacterial infection [51,52], supporting the essential role of IL-17 in the inflammatory response. IL-17 targets various cells such as endothelial cells, fibroblasts, and macrophages, leading to the production of inflammatory cytokines [53,54] (Figure 2). The key role of IL-17 in the pathogenesis of chronic inflammatory diseases including SpA as well as in host defense has also been reported [54,55]. In addition to arthritis, IL-17 has been shown to affect bone metabolism by activating the production of matrix metalloproteinases by macrophages and the receptor activator of NF-κB ligand (RANKL) presented by osteoblasts [54,56]. Furthermore, IL-17 has direct effects on osteoclasts and activates osteoclastogenesis [56]. Thus, IL-17 has been demonstrated to be involved with the pathogenesis of SpA.

**Figure 2.** Schematic overview of the role of IL-23 and IL-17 in SpA. Dendric cells (DCs) and macrophages (MΦs) produce IL-23. IL-23 induces the production of IL-17 by various cells and contributes to inflammation by upregulating the production of inflammatory cytokines such as IL-6 and TNF-α, which induces inflammation in the enthesis and joint.
