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Cytokine-modulating strategies and newer cytokine targets for arthritis therapy.

Venkatesha SH, Dudics S, Acharya B, Moudgil KD - Int J Mol Sci (2014)

Bottom Line: Furthermore, the use of anti-inflammatory cytokines or cytokine antagonists delivered via gene therapy has proven to be an effective approach to regulate autoimmunity.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, University of Maryland School of Medicine, 685 W. Baltimore Street, HSF-1, Suite 380, Baltimore, MD 21201, USA. hvshivaprasad@gmail.com.

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.

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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.
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ijms-16-00887-f001: 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.

Mentions: Cytokines serve as the mediators of cellular differentiation, inflammation, immune pathology, and regulation of immune response. A balance between pro-inflammatory and anti-inflammatory cytokines is essential for the development of a well-regulated effector immune response. The overproduction of pro-inflammatory cytokines and/or the deficiency of anti-inflammatory cytokines may lead to immune pathology [1,2,3,4,5]. The classic, well-known pro-inflammatory cytokines include tumor necrosis factor α (TNFα), interleukin-1β (IL-1β), IL-6, interferon-γ (IFN-γ) and IL-17 among others. TNFα, IL-1β and IL-6 are mainly produced by cells of myeloid origin such as macrophages and dendritic cells, whereas, IFN-γ and IL-17 are the defining cytokines for T helper 1 (Th1) and Th17 cells, respectively. Collectively, these pro-inflammatory cytokines, directly or indirectly, are involved in the differentiation and activation of pathogenic (e.g., Th17) cells, the migration of pathogenic cells into the target organ (the joints), the process of neovascularization (angiogenesis), the development and activation of osteoclasts, and the process of bone damage during the course of autoimmune arthritis [1,5]. On the other hand, the classic anti-inflammatory cytokines include IL-4 and IL-10, which display immunosuppressive activities. IL-23 and IL-27 represent additional cytokines of interest in rheumatoid arthritis (RA). IL-23 exerts pro-inflammatory activity with its ability to expand Th17 cells [6,7], whereas IL-27 acts as an anti-inflammatory cytokine in part via the inhibition of Th17 response [8,9]. The roles of most of the above-mentioned cytokines in the pathogenesis of RA are reviewed elsewhere by others and us [1,2,3,4], and are depicted in Figure 1. The salient features of three of the key pro-inflammatory cytokines (TNFα, IL-6, and IL-17) involved in arthritis are summarized below.


Cytokine-modulating strategies and newer cytokine targets for arthritis therapy.

Venkatesha SH, Dudics S, Acharya B, Moudgil KD - Int J Mol Sci (2014)

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.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4307281&req=5

ijms-16-00887-f001: 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.
Mentions: Cytokines serve as the mediators of cellular differentiation, inflammation, immune pathology, and regulation of immune response. A balance between pro-inflammatory and anti-inflammatory cytokines is essential for the development of a well-regulated effector immune response. The overproduction of pro-inflammatory cytokines and/or the deficiency of anti-inflammatory cytokines may lead to immune pathology [1,2,3,4,5]. The classic, well-known pro-inflammatory cytokines include tumor necrosis factor α (TNFα), interleukin-1β (IL-1β), IL-6, interferon-γ (IFN-γ) and IL-17 among others. TNFα, IL-1β and IL-6 are mainly produced by cells of myeloid origin such as macrophages and dendritic cells, whereas, IFN-γ and IL-17 are the defining cytokines for T helper 1 (Th1) and Th17 cells, respectively. Collectively, these pro-inflammatory cytokines, directly or indirectly, are involved in the differentiation and activation of pathogenic (e.g., Th17) cells, the migration of pathogenic cells into the target organ (the joints), the process of neovascularization (angiogenesis), the development and activation of osteoclasts, and the process of bone damage during the course of autoimmune arthritis [1,5]. On the other hand, the classic anti-inflammatory cytokines include IL-4 and IL-10, which display immunosuppressive activities. IL-23 and IL-27 represent additional cytokines of interest in rheumatoid arthritis (RA). IL-23 exerts pro-inflammatory activity with its ability to expand Th17 cells [6,7], whereas IL-27 acts as an anti-inflammatory cytokine in part via the inhibition of Th17 response [8,9]. The roles of most of the above-mentioned cytokines in the pathogenesis of RA are reviewed elsewhere by others and us [1,2,3,4], and are depicted in Figure 1. The salient features of three of the key pro-inflammatory cytokines (TNFα, IL-6, and IL-17) involved in arthritis are summarized below.

Bottom Line: Furthermore, the use of anti-inflammatory cytokines or cytokine antagonists delivered via gene therapy has proven to be an effective approach to regulate autoimmunity.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, University of Maryland School of Medicine, 685 W. Baltimore Street, HSF-1, Suite 380, Baltimore, MD 21201, USA. hvshivaprasad@gmail.com.

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.

Show MeSH
Related in: MedlinePlus