Cytokine-modulating strategies and newer cytokine targets for arthritis therapy

Abstract

Cytokines are the key mediators of inflammation in the course of autoimmune arthritis and other immune-mediated diseases. Uncontrolled production of the pro-inflammatory cytokines such as interferon-γ (IFN-γ), tumor necrosis factor α (TNFα), interleukin-6 (IL-6), and IL-17 can promote autoimmune pathology, whereas anti-inflammatory cytokines including IL-4, IL-10, and IL-27 can help control inflammation and tissue damage. The pro-inflammatory cytokines are the prime targets of the strategies to control rheumatoid arthritis (RA). For example, the neutralization of TNFα, either by engineered anti-cytokine antibodies or by soluble cytokine receptors as decoys, has proven successful in the treatment of RA. The activity of pro-inflammatory cytokines can also be downregulated either by using specific siRNA to inhibit the expression of a particular cytokine or by using small molecule inhibitors of cytokine signaling. Furthermore, the use of anti-inflammatory cytokines or cytokine antagonists delivered via gene therapy has proven to be an effective approach to regulate autoimmunity. Unexpectedly, under certain conditions, TNFα, IFN-γ, and few other cytokines can display anti-inflammatory activities. Increasing awareness of this phenomenon might help develop appropriate regimens to harness or avoid this effect. Furthermore, the relatively newer cytokines such as IL-32, IL-34 and IL-35 are being investigated for their potential role in the pathogenesis and treatment of arthritis.

Figure 1

The roles of cytokines in arthritis pathogenesis. The cytokine environment in the joints and the draining lymphoid tissue in rheumatoid arthritis is rather complex. There are multiple cell types that are present and each secretes a panel of pro-/anti-inflammatory cytokines, chemokines, or other inflammatory mediators. Each cytokine has its own role in either promoting an immune response or regulating the immune response. Moreover, one cytokine can have more than one function, known as pleiotropy, or have duality of action (both pro- and anti-inflammatory properties). Furthermore, there is redundancy meaning that there are overlapping characteristics between different cytokines (e.g., IL-6 and IL-17 being pro-inflammatory). Depending on the proportion of cell types present within the joints and the type of immune stimuli that they are exposed to, the overall milieu in the tissue is predominantly pro-inflammatory or anti-inflammatory. COX2, cyclooxygenase type 2; FLS, fibroblast-like synoviocyte; IL, interleukin; Mac, macrophage; MCP-1, monocyte chemoattractant protein 1; MHCII, major histocompatability complex class II; MMP, matrix metalloprotease; PDGF, platelet derived growth factor; RANTES, regulated on activation, normal T cell expressed and secreted; TGFβ, transforming growth factor β; Treg, T regulatory cell; VEGF, vascular endothelial growth factor. * Asterisk within the T cell denotes multiple subtypes: Th1, Th17, or Treg.

Figure 2

Diverse strategies employed to control the activity of pro-inflammatory cytokines and tissue damage. Pro-inflammatory cytokines, when produced in excess, can cause significant damage to tissues in various autoimmune diseases. Multiple approaches have been developed to prevent and ameliorate the harmful side effects of the pro-inflammatory cytokines. Anti-cytokine antibodies can inhibit the binding of the cytokines to their receptors. Decoy receptors can similarly bind the cytokines and prevent them from binding to the corresponding natural receptors on the cell surface. Gene therapy can be used to suppress the production of specific pro-inflammatory cytokines, whereas siRNAs can silence particular mRNA that encode the cytokine and thereby, prevent its production. Small molecule inhibitors can target certain pathways involved in the production of pro-inflammatory cytokines as well as inhibit their signaling abilities. Finally, anti-inflammatory cytokines help downregulate the pathogenic immune responses and subsequently inhibit further tissue damage. Paradoxically, TNFα can display anti-inflammatory properties under certain conditions.