Role of Cytokines in rheumatoid arthritis

Cytokines in rheumatoid arthritis review

Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease that is characterized by persistent intense immunological activity, local destruction of bone and cartilage, and a variety of systemic manifestations. CD4 T cells play a central role in initiating and perpetuating the chronic autoimmune response characteristic of rheumatoid inflammation. Here, you can see the briefly summary about the functions of the key cytokines of Th subsets and their roles in rheumatoid arthritis.

Cytokines in rheumatoid arthritis: IL-4

IL-4 is discovered as a T cell product distinct from IL-2 that could stimulate anti-Ig-M treated B cells to proliferate and to differentiate into IgG-secreting plasma cells. IL-4 is produced by activated T cells, mast cells, Nk cells, basophils and eosinophils.

IL-4 inhibits bone resorption through an effect on both osteoclast activity and survival and reduces the spontaneous secretion of pro-inflammatory cytokines and immunoglobulin in ex-vivo cultures pieces from the rheumatoid synovial membrane. Furthermore, IL-4 downregulates the surface expression of CD5 on Bcells and inhibits spontaneous immunoglobulin and IgM rheumatois factor production in patients with rheumatoid arthritis.

IL-4 is discovered as a T cell product distinct from IL-2 that could stimulate anti-Ig-M treated B cells to proliferate and to differentiate into IgG-secreting plasma cells. IL-4 is produced by activated T cells, mast cells, Nk cells, basophils and eosinophils.

Of importance in regulating immune responses is its ability to downregulate the activation and the inflammatory functions of monocytes and macrophages. IL-4 increase the expression of MHC class II molecules and of several cytokine inhibitors such as IL-1 receptor antagonist (IL-1Ra), soluble Il-1 receptor type II and TNF receptors while downregulating the production of the pro-inflammatory cytokines IL-1, TNF-α,IL-6, IL-8 and IL-12.

Cytokines in rheumatoid arthritis: INF-γ

Production of INF-γ is the hallmark of Th1 cells. IFN-γ id produced mainly by activated T cells and NK cells and had receptors in virtually all cells of the human body. The ability of IFN-γ to activate endothelial cells and macrophages is the basis for defining IFN-γ as a pro-inflammatory cytokine. IL-12 is the most potent inducer of IFN-γ secretion. IL-18 is also able to induce IFN-γ production from T cells. The potent pro-inflammatory cytokine activities of IFN-γ combined with its inhibitory potential for the development of Th2 cells make IFN-γ a central mediator of the signs and symptoms of chronic autoimmune inflammation.

In atopic rheumatoid arthritis patients, they had higher levels of serum IgE and peripheral blood eosinophils, but their T cells produced less IFN-γ. As allergy is the prototype Th2 disease, the occurrence of a Th2-driven inflammation might be beneficial in rheumatoid arthritis by inhibiting Th1-mediated immunity.

Cytokines in rheumatoid arthritis: IL-10

IL-10 is a homodimeric cytokine of 17kDa that was discovered as a potent inhibitor of macrophage effector functions. It-is produced by activated monocytes, NK cells, B cells and T cells. In mice, IL-10 is clearly a Th2 cytokine. In human, IL-10 can be produced by both the Th1 and Th2 subsets. Il-10 is able to ameliorate potential pathological autoimmune inflammation through the inhibition at various facets of the immune response. IL-10 inhibits the production of pro-inflammatory cytokines by macrophages, such as IL-1β, IL-6, IL8, IL-12 and THF-α, and upregulates the production if IL-1Ra and soluble p55 and p75 TNF-receptors.

In T cells, IL-10 inhibits production of IL-2 and IFN-γ and also block T cell proliferation. Thus, IL-10 has potent anti-inflammatory functions and has, consequently, been used in the treatment of experimental autoimmune disease with great success.IL-4 and IL-10 synergistically reduce joint inflammation in acute and chronic arthritis models. Thus, IL-10 might be an effective means for downregulating human chronic autoimmune inflammation by counteracting IFN-γ mediated pro-inflammatory activities.

The balance of Th1/Th2 cytokines in rheumatoid arthritis

Human CD4+ T helper cells can be divided into at least two different subsets. Th1 cells produce the pro-inflammatory cytokines IL-1, IFN-γ and LT, activate macrophages and mediate cellular immunity. Th2 effectors down-modulate macrophage activation by secretion of the anti-inflammatory cytokines IL-4 and IL-5, they promote humoral immunity and are involved in allergic inflammation. Imbalances in the ration of activated Th1 versus Th2 cells have been associated with the development of a variety of pathogenic inflammatory responses, and it has been shown that Th1-mediated immunity is associated with the pathogenesis of several organ-specific autoimmune diseases in animals. Th1 cells and their cytokines substantially promote many aspects of synovial inflammation and that interference with their activation and with the activity of their secreted cytokines might be beneficial in the treatment of rheumatoid arthritis.

In rheumatoid arthritis, convincing arguments have been provided to suggest that autoimmune rheumatoid inflammation is also driven by activated Th1 effectors without sufficient Th2 generation to downregulate inflammation. Furthermore, recent data suggest that several treatment modalities currently employed in rheumatoid arthritis, exert their immunomodulatory effect at least in part by inhibiting Th1 cell activation and/or differentiation and by favouring Th2 differentiation, thereby shifting the Th1/Th2 balance towards the Th2 direction. Thus, selective manipulation of Th cell differentiation to induce Th2 effectors might be a successful approach for interrupting ongoing and established Th1-driven chronic autoimmune diseases such as rheumatoid arthritis.

Cytokine molecules related

IFN Receptor

IL10 Family Receptor

TGF beta Family Receptor


Hendrik Schulze-koops, et al.The balance of Th1/Th2 cytokines in rheumatoid arthritis.