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Review
. 2011:2011:432595.
doi: 10.1155/2011/432595. Epub 2011 Oct 16.

Inflammatory cytokines in systemic lupus erythematosus

Kim Ohl  1 , Klaus Tenbrock
Affiliations
Review

Inflammatory cytokines in systemic lupus erythematosus

Kim Ohl et al. J Biomed Biotechnol. 2011.

Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disease of unknown origin affecting virtually all organ systems. Beyond genetic and environmental factors, cytokine imbalances contribute to immune dysfunction, trigger inflammation, and induce organ damage. The key cytokine that is involved in SLE pathogenesis is interferon alpha. Interferon secretion is induced by immune complexes and leads to upregulation of several inflammatory proteins, which account for the so-called IFN signature that can be found in the majority of SLE PBMCs. Additionally IL-6 and IFN-y as well as T-cell-derived cytokines like IL-17, IL-21, and IL-2 are dysregulated in SLE. The latter induce a T-cell phenotype that is characterized by enhanced B-cell help and enhanced secretion of proinflammatory cytokines but reduced induction of suppressive T cells and activation-induced cell death. This paper will focus on these cytokines and highlights pathophysiological approaches and therapeutic potential.

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Figures

Figure 1
Figure 1
The vicious circle of IFN signaling in SLE: ICs bind to Fc gamma RII receptors on pDCs and reach the endosomes where they are recognized by TLRs. TLRs transduce signals to the nucleus which induce transcription of IFN. IFN secretion enhances expression of its own receptor on pDCs, mDCs, and monocytes. Furthermore, IFN promotes maturation of DCs which leads to disruption of peripheral tolerance and activation of autoreactive CD4 T helper cells. The appearance of autoreactive CD4 T cells is further amplified by upregulation of CD80 and CD86 on APCs. This results in enhanced B cell help by autoreactive CD4 cells, which is again sustained by an upregulation of BAFF. The increased formation of autoreactive B cells triggers appearance of ICs and further IFN release.
Figure 2
Figure 2
Model of gp130 transsignaling. IL-6 signaling occurs by binding its membrane bound receptor (IL-6R) in target cells and subsequent dimerization of gp130 (Figure on the left). Cells which do not express IL-6R can also be susceptible to IL-6 via soluble IL-6 receptors that dimerize with membrane bound gp130 (Figure on the right).
Figure 3
Figure 3
Dysregulated cytokine expression by T cells contributes to pathogenesis of SLE. SLE T cells secrete enhanced levels of IL-17 and IL-21 compared to healthy persons. IL-17 induces secretion of chemokines and other proinflammatory cytokines and therefore participates in tissue inflammation and organ damage. IL-21 and IL-17 both promote differentiation of B cells into plasma cells and production of IgG antibodies. IL-21 further maintains and expands occurrence of Th17 cells. In contrast SLE T cells have a defective production of IL-2, which leads to reduced level of regulatory T cells and defective function of T cells, which might also be caused by IL-21. Since IL-2 is crucial for AICD, low levels of IL-2 might be responsible for reduced AICD leading to expansion of autoreactive T cells, which further trigger B-cell activation and tissue inflammation.
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