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      Glucocorticoid Receptor, Nuclear Factor κB, Activator Protein-1 and C-Jun N-Terminal Kinase in Systemic Lupus Erythematosus Patients

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          Objective: Due to the crucial role of the glucocorticoid receptor (GR), nuclear factor ĸB (NFĸB), activator protein-1 (AP-1) and c-jun N-terminal kinase (JNK) in regulating inflammatory mediators and immune responses, we investigated their potential role in systemic lupus erythematosus (SLE). Patients and Methods: Whole cell and nuclear extracts from peripheral blood lymphocytes, isolated from 25 SLE patients and 25 controls, were immunoblotted using GR, p65/NFĸB, c-fos and JNK1 antibodies. The electrophoretic mobility shift assay (EMSA) assessed GR, NFĸB and AP-1-DNA binding in nuclear aliquots. Associations with the disease state and the doses of corticosteroids administered were studied. Results: (i) SLE patients had lower GR-DNA binding (p < 0.001), NFĸB-DNA binding (p < 0.001) and whole cell c-fos (p < 0.01) but higher nuclear NFĸB (p < 0.01). (ii) SLE patients and controls had similar AP-1-DNA binding, nuclear c-fos, GR and JNK, whole cell GR, NFĸB and JNK. (iii) No differences were detected between active and non-active SLE or high- and low-dose corticosteroid patients. (iv) In SLE, increases in GR-DNA binding were associated with increases in NFĸB-DNA binding (p < 0.0001), and increases in nuclear JNK were associated with increases in AP-1-DNA binding (p < 0.01). (v) In controls, increases in GR-DNA binding were associated with increases in AP-1-DNA binding (p < 0.001). Conclusion: We suggest disturbed GR, NFĸB, AP-1 and JNK signaling in SLE, characterized by a reduced GR- and NFĸB-DNA binding, a significant association between GR-mediated and NFĸB-driven pathways, and a significant correlation between nuclear JNK- and AP-1-driven pathways. These disturbances may contribute to abnormal cytokine production and the etiopathogenesis of SLE.

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          Most cited references 30

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          Rapid detection of octamer binding proteins with 'mini-extracts', prepared from a small number of cells.

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            JNK1: a protein kinase stimulated by UV light and Ha-Ras that binds and phosphorylates the c-Jun activation domain.

            The ultraviolet (UV) response of mammalian cells is characterized by a rapid and selective increase in gene expression mediated by AP-1 and NF-kappa B. The effect on AP-1 transcriptional activity results, in part, from enhanced phosphorylation of the c-Jun NH2-terminal activation domain. Here, we describe the molecular cloning and characterization of JNK1, a distant relative of the MAP kinase group that is activated by dual phosphorylation at Thr and Tyr during the UV response. Significantly, Ha-Ras partially activates JNK1 and potentiates the activation caused by UV. JNK1 binds to the c-Jun transactivation domain and phosphorylates it on Ser-63 and Ser-73. Thus, JNK1 is a component of a novel signal transduction pathway that is activated by oncoproteins and UV irradiation. These properties indicate that JNK1 activation may play an important role in tumor promotion.
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              The interplay between the glucocorticoid receptor and nuclear factor-kappaB or activator protein-1: molecular mechanisms for gene repression.

              The inflammatory response is a highly regulated physiological process that is critically important for homeostasis. A precise physiological control of inflammation allows a timely reaction to invading pathogens or to other insults without causing overreaction liable to damage the host. The cellular signaling pathways identified as important regulators of inflammation are the signal transduction cascades mediated by the nuclear factor-kappaB and the activator protein-1, which can both be modulated by glucocorticoids. Their use in the clinic includes treatment of rheumatoid arthritis, asthma, allograft rejection, and allergic skin diseases. Although glucocorticoids have been widely used since the late 1940s, the molecular mechanisms responsible for their antiinflammatory activity are still under investigation. The various molecular pathways proposed so far are discussed in more detail.

                Author and article information

                S. Karger AG
                March 2007
                29 March 2007
                : 13
                : 4
                : 194-204
                Departments of aBiological Chemistry and bPathophysiology, University of Athens Medical School, and cDepartment of Animal Breeding, Agricultural University of Athens, Athens, Greece
                100474 Neuroimmunomodulation 2006;13:194–204
                © 2006 S. Karger AG, Basel

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                Page count
                Figures: 2, Tables: 3, References: 53, Pages: 11
                Original Paper


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