**3. The short overview of the role of cytokines in rheumatoid arthritis**

Inflammatory diseases such as arthritis share some common clinical characteristics including the degradation of the connective tissue and bone. The rheumatoid arthritis (RA) is the chronic inflammatory state characterized by synovial inflammation and progressive joint cartilage and bone destruction. The chronic inflammatory process with the continuous stimulation of synoviocytes directly leads to the hypertrophy of the synovial membrane and bone resorption. The development of RA is associated with the uncontrolled production of pro-inflammatory cytokines by the activated synoviocytes and the antigen stimulated lymphocytes. The cytokines mentioned below play significant role while both the development of the RA and the surgical stress response

**Interleukin -1** (IL-1) is produced by macrophages, monocytes and endothelial cells. The secretion of IL-1 is triggered by many factors including TNF and complements. The interleukin 1 (IL-1) family includes two forms of IL-1 (IL-1α, IL-1β), IL-1 receptors (RI, RII) and IL-1 receptor antagonist (IL-1Ra). Interestingly, the recent results of studies suggested that the interleukin-1α (IL-1α) plays the neuroprotective role inside the damaged brain cells (Clausen et al. 2011). During the early stages of shock, the IL-1β is secreted from liver cells after the stimulation of noradrenalin, which may be the example of the relationship between neuro-immune systems (Zhou et al., 2005). In rheumatoid arthritis patients, the plasma and the synovial fluid concentrations of IL-1 are elevated and are correlated with various parameters of disease severity. The production of endogenous IL-1Ra appears to be insufficient to counteract IL-1 activity (Pritchard et al., 2008). It is also appeared that IL-1 has a significant impact on the process of damage and degradation of the cartilage in the pathogenesis of arthritis (Aida et al., 2006).

**Interleukin -6** (IL-6) is secreted by many cells types. In RA joints synoviocytes are the major source of IL-6. The production of IL-6 is induced by IL-1 and TNF. IL-6 is involved in development of immune response, inflammation and haemotopoiesis. For instance, it regulates the growth and differentiation of the lymphocytes T and is considered as the a critical factor for B cells proliferation and stimulation of the immunoglobulin production. The serum elevation of IL-6 is noticeable in face of infections, inflammation and injury when IL-6 induces fever and production of acute phase proteins. Silverman et al. (28) recently demonstrated that IL-6 can directly stimulate the corticosteroid secretion from the adrenal cortex and there is evidence suggesting that it can also stimulate ACTH secretion from the pituitary gland (Silverman et al., 2004). IL-6 has also anti -inflammatory function by stimulation of monocytes to release anti inflammatory cytokines such as IL-10, IL-1Ra.

inducers of acute phase proteins (APPs). Among some (e.g. C-reactive protein (CRP), complement factors, fibrinogen, plazminogen CAPPs) are up- regulated while production of

The long-lasting inflammatory process called chronic inflammatory response, itself is a organism wasting disease. The presence of the chronic inflammatory state is immensely associated with the dysfunction of the neuroendocrine-immune system. The neuroendocrine -immune disturbances also play an crucial role in the development of human autoimmune diseases such as the rheumatoid arthritis and the systemic lupus erythematous and the others. During the chronic inflammatory stage all these systems

Inflammatory diseases such as arthritis share some common clinical characteristics including the degradation of the connective tissue and bone. The rheumatoid arthritis (RA) is the chronic inflammatory state characterized by synovial inflammation and progressive joint cartilage and bone destruction. The chronic inflammatory process with the continuous stimulation of synoviocytes directly leads to the hypertrophy of the synovial membrane and bone resorption. The development of RA is associated with the uncontrolled production of pro-inflammatory cytokines by the activated synoviocytes and the antigen stimulated lymphocytes. The cytokines mentioned below play significant role while both the

**Interleukin -1** (IL-1) is produced by macrophages, monocytes and endothelial cells. The secretion of IL-1 is triggered by many factors including TNF and complements. The interleukin 1 (IL-1) family includes two forms of IL-1 (IL-1α, IL-1β), IL-1 receptors (RI, RII) and IL-1 receptor antagonist (IL-1Ra). Interestingly, the recent results of studies suggested that the interleukin-1α (IL-1α) plays the neuroprotective role inside the damaged brain cells (Clausen et al. 2011). During the early stages of shock, the IL-1β is secreted from liver cells after the stimulation of noradrenalin, which may be the example of the relationship between neuro-immune systems (Zhou et al., 2005). In rheumatoid arthritis patients, the plasma and the synovial fluid concentrations of IL-1 are elevated and are correlated with various parameters of disease severity. The production of endogenous IL-1Ra appears to be insufficient to counteract IL-1 activity (Pritchard et al., 2008). It is also appeared that IL-1 has a significant impact on the process of damage and degradation of the cartilage in the

**Interleukin -6** (IL-6) is secreted by many cells types. In RA joints synoviocytes are the major source of IL-6. The production of IL-6 is induced by IL-1 and TNF. IL-6 is involved in development of immune response, inflammation and haemotopoiesis. For instance, it regulates the growth and differentiation of the lymphocytes T and is considered as the a critical factor for B cells proliferation and stimulation of the immunoglobulin production. The serum elevation of IL-6 is noticeable in face of infections, inflammation and injury when IL-6 induces fever and production of acute phase proteins. Silverman et al. (28) recently demonstrated that IL-6 can directly stimulate the corticosteroid secretion from the adrenal cortex and there is evidence suggesting that it can also stimulate ACTH secretion from the pituitary gland (Silverman et al., 2004). IL-6 has also anti -inflammatory function by stimulation of monocytes to release anti inflammatory cytokines such as IL-10, IL-1Ra.

**3. The short overview of the role of cytokines in rheumatoid arthritis** 

others (albumin, transferrin, antitrombin) decreased (Engler, 1995).

development of the RA and the surgical stress response

pathogenesis of arthritis (Aida et al., 2006).

have become deficient.

The receptor for IL-6 consists of two proteins: the chain α, that can be expressed on membrane cell or in soluble form and subunit gp130 that belongs to proteins receptor for IL-6 in membrane cells. In contrast to most cytokines (e.g. TNF) soluble IL-6 acts as agonist but not antagonist.

IL-6 play important role in many inflammatory diseases. RA is characterized by the overproduction of IL-6. The very high level of IL-6 in the serum and synovial fluid is involved and correlated with clinical and laboratory indices (Lisowska et al., Dec 2007; Nishimoto, 2006).

The secretion of both, described cytokines (IL-1, IL-6) is stimulated by tumor necrosis factor (TNF).

**Tumor necrosis factor -** is produced by monocytes, macrophages, neutrophils, mast cells, fibroblasts, and the activated T cells.

TNF is a number of TNF family. The binding of TNF to its receptors TNFR1 and TNFR2 cause multiple effects including: the increase of inflammatory mediators (e.g. nitric oxide (NO), arachidonic acid pathway, the platelet activating factor (PAF) and intracellular adhesion molecules (ICAM)) (Lenzab et all., 2007; Lenz et al., 2007).

The increased expression of TNF occurs in the synovium of rheumatoid arthritis patients with following induction of its cells activities. TNF is thought to play the role key role in the local activation of immune cells and joint cartilage and bone destruction. Together with IL-1 TNF-α also induce an expression of adhesion molecules on the surface of the endothelial cells which is particularly important during the first stages of inflammation, because it enables the infiltration of leukocytes from the bloodstream into the tissues.

**Transforming growth factor –β** (TGF–β) belongs to the TGF family cytokines. The TGF-β plays crucial role in inhibition of the inflammatory reaction and autoimmune diseases. The TGF–β plays the essential role in control and regulation of the lymphocytes proliferation, differentiation and survival. The TGF function including the antiproliferation activity on the T, B lymphocytes that can initiate and aggravate the disease. The TGF-β is also an important regulator of the B cell activation and differentiation (Li et al., 2006). Most of the produced cytokines are not stored at all. Nevertheless there are produced and released as needed. However, transforming growth factor β is stored inside the mast cells and platelets *(*Sheran & Hall, 1997).
