Altered AKT1 and MAPK1 Gene Expression on Peripheral Blood Mononuclear Cells and Correlation with T-Helper-Transcription Factors in Systemic Lupus Erythematosus Patients

Sonia Garcia-Rodriguez,Pilar Navarro,Raquel Ríos-Fernandez,Jaime Sancho,Norberto Ortego-Centeno,Salvador Arias-Santiago,Jose-Luis Callejas-Rubio,Mercedes Zubiaur,Esther Zumaquero

doi:10.1155/2012/495934

Abstract

Kinases have been implicated in the immunopathological mechanisms of Systemic Lupus Erythematosus (SLE). v-akt murine-thymoma viral-oncogene-homolog 1 (AKT1) and mitogen-activated-protein-kinase 1 (MAPK1) gene expressions in peripheral mononuclear cells from thirteen SLE patients with inactive or mild disease were evaluated using quantitative real-time reverse-transcription polymerase-chain-reaction and analyzed whether there was any correlation with T-helper (Th) transcription factors (TF) gene expression, cytokines, and S100A8/S100A9-(Calprotectin). Age- and gender-matched thirteen healthy controls were examined. AKT1 and MAPK1 expressions were upregulated in SLE patients and correlated with Th17-(Retinoic acid-related orphan receptor (ROR)-C), T-regulatory-(Treg)-(Transforming Growth Factor Beta (TGFB)-2), and Th2-(interleukin (IL)-5)-related genes. MAPK1 expression correlated with Th1-(IL-12A, T-box TF-(T-bet)), Th2-(GATA binding protein-(GATA)-3), and IL-10 expressions. IL-10 expression was increased and correlated with plasma Tumor Necrosis Factor (TNF)-α and Th0-(IL-2), Th1-(IL-12A, T-bet), GATA3, Treg-(Forkhead/winged-helix transcription factor- (FOXP)-3), and IL-6 expressions. FOXP3 expression, FOXP3/RORC, and FOXP3/GATA3 expression ratios were increased. Plasma IL-1β, IL-12(p70), Interferon-(IFN)-γ, and IL-6 cytokines were augmented. Plasma IL-1β, IL-6, IL-2, IFN-γ, TNF-α, IL-10, and IL-13 correlated with C-reactive protein, respectively. Increased Calprotectin correlated with neutrophils. Conclusion, SLE patients presented a systemic immunoinflammatory activity, augmented AKT1 and MAPK1 expressions, proinflammatory cytokines, and Calprotectin, together with increased expression of Treg-related genes, suggesting a regulatory feedback opposing the inflammatory activity.

Highlights

Systemic Lupus Erythematosus (SLE) is a chronic inflammatory autoimmune disease most common in women of reproductive age [1], characterized by a relapsing/remitting course and the involvement of multiple organs, including skin, kidneys, and central nervous system
Kinases have been implicated in the immunopathological mechanisms of Systemic Lupus Erythematosus (SLE). v-akt murinethymoma viral-oncogene-homolog 1 (AKT1) and mitogen-activated-protein-kinase 1 (MAPK1) gene expressions in peripheral mononuclear cells from thirteen SLE patients with inactive or mild disease were evaluated using quantitative real-time reversetranscription polymerase-chain-reaction and analyzed whether there was any correlation with T-helper (Th) transcription factors (TF) gene expression, cytokines, and S100A8/S100A9-(Calprotectin)
AKT1 (7.82 (2.61–11.45)), MAPK1 (19.47 (8.71–33.45)), and ZAP70 (1.98 (1.14–3.66)) relative gene expressions levels were significantly augmented in peripheral blood mononuclear cells (PBMC) from SLE patients (n = 13) as compared with controls (Wilcoxon Signed Rank test: P = 0.0064, P = 0.0012, and P = 0.0024, resp.) (Figure 1(a))

Summary

Introduction

Systemic Lupus Erythematosus (SLE) is a chronic inflammatory autoimmune disease most common in women of reproductive age [1], characterized by a relapsing/remitting course and the involvement of multiple organs, including skin, kidneys, and central nervous system. In SLE bone marrow mononuclear cells, Nakou et al [6] identified central gene regulators implicated in disease pathogenesis which include activation of multiple kinase pathways (MAPK/extracellular regulated MAP kinase (ERK), Signal Transducer and Activator of Transcription (STAT), Mediators of Inflammation. AKT1 serine/threonine kinase is a key downstream target of PI3 K signaling pathway, and plays a role in the differentiation of peripheral B cells and in T cell homeostasis [7,8,9,10]. Upregulated activity of AKT kinases has been documented in B cells from SLE patients [11]. MAPK/ERK kinases play a significant role in immune-mediated inflammatory responses and are involved in the maintenance of T-cell tolerance that fails in SLE patients [4, 12]. In SLE T cells, alterations in kinases pathways such as the spleen tyrosine kinase (Syk) signaling patterns have been documented by Krishnan et al [15]

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