Elsevier

Cytokine

Volume 73, Issue 2, June 2015, Pages 326-334
Cytokine

The role of cytokines in the pathogenesis of cutaneous lupus erythematosus

https://doi.org/10.1016/j.cyto.2015.01.031Get rights and content

Highlights

  • The pathogenesis of cutaneous lupus erythematosus (CLE) is multifactorial.

  • Cytokines are increased in the skin in CLE and are important in CLE’s pathogenesis.

  • Ultraviolet (UV) light directly increases inflammatory cytokine production in CLE.

Abstract

Cutaneous lupus erythematosus (CLE) is an inflammatory disease with a broad range of cutaneous manifestations that may be accompanied by systemic symptoms. The pathogenesis of CLE is complex, multifactorial and incompletely defined. Below we review the current understanding of the cytokines involved in these processes. Ultraviolet (UV) light plays a central role in the pathogenesis of CLE, triggering keratinocyte apoptosis, transport of nucleoprotein autoantigens to the keratinocyte cell surface and the release of inflammatory cytokines (including interferons (IFNs), tumor necrosis factor (TNF)-α, interleukin (IL)-1, IL-6, IL-8, IL-10 and IL-17). Increased IFN, particularly type I IFN, is central to the development of CLE lesions. In CLE, type I IFN is produced in response to nuclear antigens, immune complexes and UV light. Type I IFN increases leukocyte recruitment to the skin via inflammatory cytokines, chemokines, and adhesion molecules, thereby inducing a cycle of cutaneous inflammation. Increased TNFα in CLE may also cause inflammation. However, decreasing TNFα with an anti-TNFα agent can induce CLE-like lesions. TNFα regulates B cells, increases the production of inflammatory molecules and inhibits the production of IFN-α. An increase in the inflammatory cytokines IL-1, IL-6, IL-10, IL-17 and IL-18 and a decrease in the anti-inflammatory cytokine IL-12 also act to amplify inflammation in CLE. Specific gene mutations may increase the levels of these inflammatory cytokines in some CLE patients. New drugs targeting various aspects of these cytokine pathways are being developed to treat CLE and systemic lupus erythematosus (SLE).

Section snippets

Introduction to cutaneous lupus erythematosus

Lupus erythematosus (LE) encompasses a broad range of cutaneous symptoms including malar rash, discoid rash, photosensitivity and oral ulcers as well as systemic symptoms such as arthritis, renal disease, abnormal serologies and hematologic disease. Patients may have cutaneous lupus erythematosus (CLE), systemic lupus erythematosus (SLE) or both. The American College of Rheumatology defines SLE as the presence of at least four of eleven diagnostic criteria. The prevalence of SLE varies

The pathogenesis of CLE

The pathogenesis of CLE is multifactorial and incompletely understood. It involves ultraviolet (UV) light, keratinocyte apoptosis, cytokine release, B cell hyperactivity, and activation of T cells and dendritic cells. Cytokines play an important role in the pathogenesis of CLE. Cytokines induce and inhibit immune cells and each other. Their roles may be different in the various CLE subtypes.

Cytokines are grouped into two functional classes: T-helper 1 (Th1) cell-produced cytokines and T-helper

Key points

  • UV light directly increases the levels of TNFα and certain types of interferon and interleukin. These cytokines are important in the pathogenesis of CLE. They mediate the immune cell dysfunction, tissue inflammation and tissue injury present in CLE.

  • UV light induces keratinocyte apoptosis, which may increase the release of cytokines and autoantigens.

  • Keratinocyte necrosis and the action of UV light on keratinocytes displace nucleoproteins from inside the cell to the cell surface. Antibodies bind

Key points

  • Increased IFN, especially type I IFN, plays an important role in the pathogenesis of CLE.

  • In CLE, plasmacytoid dendritic cells (pDCs) produce type I IFN in response to nuclear antigens, immune complexes and UV light. Type I IFN increases leukocyte recruitment to the skin via inflammatory cytokines, chemokines and adhesion molecules. Type I IFN also upregulates the production of cytotoxic proteins. In total, these actions induce and propagate cutaneous inflammation.

  • Mutations in the IFN regulatory

Key points

  • TNFα is increased in the serum and skin of CLE patients.

  • Keratinocytes produce TNFα in response to UV light and inflammatory cytokines, particularly IL-1α, IL-18 and IFN-γ.

  • In CLE, high levels of TNFα increase the production of inflammatory cytokines, chemokines and adhesion molecules, which recruit inflammatory cells into the skin.

  • TNFα also activates B cells to produce antibodies and increases the expression of nuclear antigens on the keratinocyte surface.

  • The −308A TNFα promoter polymorphism is

Key points

  • Many inflammatory interleukins play important roles in the pathogenesis of CLE.

  • Increased levels of IL-6 and IL-10 in CLE may cause B cell hyperactivity.

  • Decreased IL-12 levels in LE enable increased humoral immune responses and UV-induced keratinocyte apoptosis.

  • IL-17 likely contributes to the increased production of inflammatory cytokines and chemokines in CLE.

  • High levels of IL-18 and the IL-18 receptor in CLE increase TNFα production, decrease IL-12 production and trigger keratinocyte death.

  • New

Conclusions

Many studies point to cytokines as important factors in the pathogenesis of CLE. IFNs, TNFα and ILs all play significant roles. The actions and interactions of these cytokines in CLE are complex. The cytokine pathways are impacted by UV light, genetic and other environmental factors. They are further complicated in that they may vary with CLE subtype. Current research is continuing to expand our knowledge of these pathways and identify potential targets for the treatment of CLE.

Acknowledgements

This material is supported by the Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development and a VA Merit Review grant to VPW.

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