Altered Expression of TNF-α Signaling Pathway Proteins in Systemic Lupus Erythematosus

Zhu, Lang-Jing; Landolt-Marticorena, Carolina; Li, Timothy; Yang, Xiao; Yu, Xueqing; Gladman, Dafna D.; Urowitz, Murray B.; Fortin, Paul R.; Wither, Joan E.

doi:10.3899/jrheum.091123

Cited by 31 publications

(21 citation statements)

References 43 publications

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“…However, in MRL/lpr mice, an increased expression of TNF was observed in the serum and in the kidney tissue (35). Human studies involving adult patients showed increased serum levels of TNF with (10,11) or without (36) association with disease activity. Another study presented high levels of TNF in patients with inactive disease, suggesting a protective effect of this cytokine in SLE (9).…”

Section: Discussionmentioning

confidence: 99%

Cytokine profile in childhood-onset systemic lupus erythematosus: a cross-sectional and longitudinal study

Cavalcanti

Santos

Mesquita

et al. 2017

Braz J Med Biol Res

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Childhood-onset systemic lupus erythematosus (cSLE) exhibits an aggressive clinical phenotype and severe complications. This could be due to a pro-inflammatory cytokine milieu. Therefore, we determined plasma levels of Th1 (IL-2, IFN-γ, TNF), Th2 (IL-4), Th17 (IL-17A, IL-6), and Treg (IL-10) cytokines in a cohort of cSLE patients and healthy controls, and we evaluated the association between these cytokines and disease activity. We conducted a cross-sectional study with 51 cSLE patients from two pediatric rheumatology services. Ten cSLE patients participated in a longitudinal follow-up study. Blood samples were collected from the same patient during active and inactive disease. Disease activity was evaluated according to SLE Disease Activity Index 2000 (SLEDAI-2K). Cytokines levels were measured by cytometric bead array technique. cSLE patients had higher IL-6 (P<0.001) and IL-10 (P<0.001) levels than healthy controls. Patients with active disease had higher IL-6 and IL-10 levels than patients with inactive disease (P=0.001 and P=0.014, respectively) and the control group (both P<0.001). IL-6 (P=0.022), IL-10 (P=0.013), and IL-17A (P=0.041) levels were significantly higher during active than inactive disease. Linear regression analysis revealed IL-6 (P=0.002, 95%CI=0.006-0.025) and IL-10 (P=0.01 95%CI=0.021-0.150) as independent factors for increased SLEDAI-2K. IL-6, IL-10, and IL-17A are candidate biomarkers for disease activity in cSLE patients. This is the first longitudinal study to support their pivotal role in the pathogenesis of the disease.

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Section: Discussionmentioning

confidence: 99%

Cytokine profile in childhood-onset systemic lupus erythematosus: a cross-sectional and longitudinal study

Cavalcanti

Santos

Mesquita

et al. 2017

Braz J Med Biol Res

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“…Expression of PD-L1 may also be influenced by the availability of receptors and inducible signaling molecules and transcription factors in the TNF receptor signaling pathway. TNF receptor expression is reportedly normal in SLE, though decreased expression of TNF-α signaling proteins in SLE patients has been reported4142, and could account for the decreased PD-L1 induction observed in unresponsive SLE monocytes from some patients, although most patient monocytes respond well to TNF-α. Anti-TNF-α therapy is effective in treating rheumatoid arthritis, auto-inflammatory diseases, and some SLE patients.…”

Section: Discussionmentioning

confidence: 99%

TNF-α and TGF-β Counter-Regulate PD-L1 Expression on Monocytes in Systemic Lupus Erythematosus

Ou¹,

Wiedeman

Stevens

2012

Sci Rep

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Monocytes in patients with systemic lupus erythematosus (SLE) are hyperstimulatory for T lymphocytes. We previously found that the normal program for expression of a negative costimulatory molecule programmed death ligand-1 (PD-L1) is defective in SLE patients with active disease. Here, we investigated the mechanism for PD-L1 dysregulation on lupus monocytes. We found that PD-L1 expression on cultured SLE monocytes correlated with TNF-α expression. Exogenous TNF-α restored PD-L1 expression on lupus monocytes. Conversely, TGF-β inversely correlated with PD-L1 in SLE and suppressed expression of PD-L1 on healthy monocytes. Therefore, PD-L1 expression in monocytes is regulated by opposing actions of TNF-α and TGF-β. As PD-L1 functions to fine tune lymphocyte activation, dysregulation of cytokines resulting in reduced expression could lead to loss of peripheral T cell tolerance.

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“…Other studies, however, have shown otherwise. One study demonstrated that elevated TNFα plasma levels do not correlate with SLE disease activity, and another study showed that TNFα levels were actually higher in patients with inactive disease, suggesting a protective role for TNFα in SLE [42,43]. Differences in patient characteristics, assays for TNFα, and study designs probably each contribute to the somewhat inchoate picture that emerges, highlighting the pleiotropic and oftentimes unpredictable nature of TNFα.…”

Section: Tumor Necrosis Factor Alphamentioning

confidence: 99%

Cytokine disturbances in systemic lupus erythematosus

2011

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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.

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Altered Expression of TNF-α Signaling Pathway Proteins in Systemic Lupus Erythematosus

Abstract: Patients with SLE had altered expression of TNF-related signaling molecules, suggesting that there may be an imbalance in TNF-alpha signaling favoring cellular activation as opposed to proapoptotic pathways.

Cited by 31 publications

References 43 publications

Cytokine profile in childhood-onset systemic lupus erythematosus: a cross-sectional and longitudinal study

Cytokine profile in childhood-onset systemic lupus erythematosus: a cross-sectional and longitudinal study

TNF-α and TGF-β Counter-Regulate PD-L1 Expression on Monocytes in Systemic Lupus Erythematosus

Cytokine disturbances in systemic lupus erythematosus

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