**5. Conclusion**

The changes in synovial joints with RA begin with inflammatory cell migration. T cell activation results in chronic inflammation and extra cellular matrix protein production by fibroblast-like synoviocytes. Macrophages transform into bone resorptive osteoclast cells and erode both joint cartilage and bone. In response to this, osteoblast cells mature and produce bone matrix. This leads to healing of joint destruction. IL-12 family cytokines can influence the responses produced by T cells and fibroblast like synoviocytes, and thus influence bone remodelling within inflamed joints. IL-12 family cytokines also bind to osteoblast and osteoclast precursors to either promote or suppress bone formation and erosion. Although IL-12 family cytokines have protein homology, with certain members sharing the same protein subunits, its functions in T cell induced inflammation and bone loss remain distinctly different (Table 1). Unlike IL-35, which suppresses the inflammatory joint response in RA, IL-12, IL-23 and IL-27 promote it. The mechanisms of action behind some of these cytokines are known whilst others are waiting to be uncovered. IL-12 drives a Th1 response whereas IL-23 promotes a Th17 response. These T cell responses lead to chronic joint inflammation. IL-12 is also a potent inducer of IFN production. The immune suppression role of IFN in osteoclastogenesis deems IL-12 to have a protective role against joint destruction caused by RA. On the other hand, IL-23 promotes joint inflammation and osteoclastogensis thereby causing bone erosion. IL-27 stimulates fibroblast like synoviocytes to produce a number of inflammatory factors that trigger joint inflammation. IL-27 also suppresses Th17 and therefore prevents bone loss in RA. The discovery of IL-35 in recent years has spawned a new area of research. This novel cytokine suppresses T cell activation and has impressive therapeutic potential against joint inflammation in RA. Its role against bone loss is unknown and requires further investigation. The role of IL-12 family cytokines in the regulation of osteoblast functions is another area in need of research. Bone erosion and joint destruction are debilitating and irreversible consequences of RA. Further exploration of IL-12 family cytokines (in particular IL-35) and their role in osteoclastogenesis needs to be undertaken without delay. Only then will the therapeutic potential of IL-35 be ready and safe to test in humans. With new therapies against RA, and potentially other autoimmune disorders, the future looks bright in this field of research.

#### **6. References**

52 Rheumatoid Arthritis – Etiology, Consequences and Co-Morbidities

effects of IL-27 on osteoclast formation are either direct (on osteoclast precursors) or indirect (via T cells). IL-27 acts on osteoclast precursor cells to down regulate RANK expression and suppress RANKL induced cell signalling (Kalliolias et al., 2010). IL-27 inhibits oseteoclastogensesis through blockade of M-CSF cell signalling via STAT1 dependent mechanisms (Furukawa et al., 2009). CD4+ T cells produce cell surface and soluble RANKL to promote osteoclast formation in joint inflammation (Kamiya et al., 2011). IL-27 suppresses both cell surface and soluble RANKL expressions in CD4+ T cells through suppression of the STAT3 dependent mechanism, rather than STAT1 (Kamiyaet al., 2011). These results suggest

IL-27 also acts on osteoblast cells. Osteoblasts express both receptor chains (gp130 and WSX-1) for IL-27 signalling (Sims and Walsh, 2010). Cultures of human osteoblast cells in a medium containing IL-27 for 14 days showed increased production of osteoblast terminal markers, alkaline phosphatase and bone nodules (Cocco et al., 2010). Results published by a number of independent studies have shown IL-27 to protect the joint from damage in

The role of IL-35 in inflammatory bone loss is poorly understood and is yet to be studied. IL-35 is capable of suppressing IL-17 production by Th17 cells (Niedbala et al., 2007; Wei et al., 2011). Both IL-27 and IL-35 appear to play salient roles in the protection against joint damage in RA. IL-35 has strong therapeutic potential in the treatment of arthritis in CIA mouse models. In order to further this potential, urgent attention on studies investigating

**inflammation**

**Osteoclast formation**

Suppress ?

**Osteoblast maturation**

that IL-27 suppress osteoclastogenesis indirectly, via T cells.

inflammatory joint disease of CIA mice (Niedbala et al., 2008).

**Cytokines CD4+ T cell Effects on Joint**

IL-27 Th1 Promote or

the biological functions of IL-35 in the control of RA bone loss must be paid.

IL-12 Th1 Promote Suppress ?

IL-23 Th17 Promote Promote ?

IL-35 Treg Suppress ? ?

Table 1. Summary the effects of IL-12 family cytokines in joint inflammation and bone

Suppress

The changes in synovial joints with RA begin with inflammatory cell migration. T cell activation results in chronic inflammation and extra cellular matrix protein production by fibroblast-like synoviocytes. Macrophages transform into bone resorptive osteoclast cells and erode both joint cartilage and bone. In response to this, osteoblast cells mature and produce bone matrix. This leads to healing of joint destruction. IL-12 family cytokines can

remodelling of rheumatoid arthritis.

**5. Conclusion** 


IL-12 Family Cytokines in Inflammation and Bone Erosion of Rheumatoid Arthritis 55

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**4** 

*Poland* 

**The Role of Neutrophils in Rheumatoid** 

Michal Gajewski1, Przemyslaw Rzodkiewicz1,2 and Slawomir Maslinski1,2

*2Department of General and Experimental Pathology, Warsaw Medical University, Warsaw,* 

Essential cells of innate immunity, neutrophils are often considered to be a homogenous population of terminally differentiated cells (Chakravarti et al., 2009). These cells represent the body's primary line of defence against invading pathogens such as bacteria, and constitute 40-60% of the white blood cell population. Neutrophils are short-lived polymorphonuclear phagocytes. They are known as first-responding inflammatory cells migrating towards the site of inflammation (Chakravarti et al., 2009**;** Edwards et al., 1997). In the circulation of healthy adults, neutrophils exist in a resting state, which ensures that their toxic intracellular contents are not accidentally released to damage host tissues. Neutrophils become activated by agents that include bacterial products and cytokines or chemokines, such as TNF-α, IL-8 or IFN-γ. The primed neutrophils are then mobilized to the site of infection or inflammation and encounter activating signals to trigger bacterial killing.

It must be noted, that the functions of resting blood neutrophils and primed neutrophils may be very different. Thus, many of the regulatory functions of macrophages are shared by primed (but not resting) neutrophils (Wright et al., 2010). For this reason, *in vitro* experiments using freshly isolated blood neutrophils often fail to recognize the full

In a chronic inflammatory process, such as rheumatoid arthritis (RA), large numbers of neutrophils are attracted across the synovial membrane, and become activated. The number of neutrophils in synovial fluid (SF) of patients with RA can reach 5x10-9 (Edwards et al., 1997). Neutrophils possess a range of potent proteinases and hydrolases, and have the ability to generate a series of reactive oxygen intermediates (ROI) via the combined activities of NADPH (reduced form) oxidase and myeloperoxidase (MPO) (Robinson et al., 1992; Duluray et al., 1990; Nurcombe et al., 1991a). If the neutrophils are not efficiently depleted, their production of inflammatory mediators, such as ROI, could prolong the inflammatory reaction. In fact, inappropriate release of ROI from activated neutrophils is responsible for joint damage observed in RA (Edwards et al., 1997). Beside ROI and inflammatory

**1. Introduction** 

(Wright et al., 2010; Cascao et al., 2009)

functional repertoire and capacity of neutrophils.

**2. Oxidative metabolism of neutrophils** 

**Arthritis – Experiments** *In Vitro***:** 

*1Department of Biochemistry, Institute of Rheumatology, Warsaw,* 

**A Change of Conception?** 

