Abstract
The pathogenesis of systemic lupus erythematosus (SLE) is complex, and the resulting disease manifestations are heterogeneous. Cytokine dysregulation is pervasive, and their protein and gene expression profiles may serve as markers of disease activity and severity. Importantly, biologic agents that target specific cytokines may represent novel therapies for SLE. Four cytokines (IL-6, TNFα, IFNα, and BLyS) are being evaluated as therapeutic targets in SLE. The present review will examine the roles of each of these cytokines in murine and human SLE, and will summarize results from clinical trials of agents that target these cytokines.
Highlights
Cytokines collectively play key roles in the regulation of systemic inflammation, local tissue damage, and immunomodulation
We focus on four cytokines that have received great attention either as candidate biomarkers for disease activity and/or as candidate targets of novel biologic agents
General biology of TNFα TNFα is expressed as a 26 kDa transmembrane protein that can be cleaved by TNFα-converting enzyme to release a 17 kDa soluble protein [25]
Summary
Cytokines collectively play key roles in the regulation of systemic inflammation, local tissue damage, and immunomodulation. Exogenous IL-6 increases IgG anti-DNA autoantibody production by B cells isolated from clinically affected BWF mice, whereas neutralization of IL-6 via either addition of an anti-IL-6 mAb or macrophage depletion decreases production of such autoantibodies [4,5,6]. Building on these ex vivo findings, administration of human IL-6 to 6-month-old female BWF mice promoted accelerated membranoproliferative glomerulonephritis associated with marked upregulation of mesangial MHC class II antigens and glomerular intercellular adhesion molecule-1 (ICAM-1) expression. Additional studies are clearly needed before tocilizumab or other IL-6 antagonists can be considered viable therapeutics in human SLE
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