Glucocorticoid receptor, nuclear factor kappaB, activator protein-1 and C-jun N-terminal kinase in systemic lupus erythematosus patients.
OBJECTIVE
Due to the crucial role of the glucocorticoid receptor (GR), nuclear factor kappaB (NFkappaB), 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).


METHODS
Whole cell and nuclear extracts from peripheral blood lymphocytes, isolated from 25 SLE patients and 25 controls, were immunoblotted using GR, p65/NFkappaB, c-fos and JNK1 antibodies. The electrophoretic mobility shift assay (EMSA) assessed GR, NFkappaB 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), NFkappaB-DNA binding (p < 0.001) and whole cell c-fos (p < 0.01) but higher nuclear NFkappaB (p < 0.01). (ii) SLE patients and controls had similar AP-1-DNA binding, nuclear c-fos, GR and JNK, whole cell GR, NFkappaB 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 NFkappaB-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).


CONCLUSIONS
We suggest disturbed GR, NFkappaB, AP-1 and JNK signaling in SLE, characterized by a reduced GR- and NFkappaB-DNA binding, a significant association between GR-mediated and NFkappaB-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.
Oikonomidou
Olga
O
Department of Biological Chemistry, University of Athens Medical School, Goudi, Athens, Greece.
Vlachoyiannopoulos
Panayiotis G
PG
Kominakis
Antonios
A
Kalofoutis
Anastasios
A
Moutsopoulos
Haralampos M
HM
Moutsatsou
Paraskevi
P
D000328:Adult; D015153:Blotting, Western; D004247:DNA / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D006801:Humans; D015151:Immunoblotting; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008180:Lupus Erythematosus, Systemic / Q000378:metabolism*; D008214:Lymphocytes / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000378:metabolism*
D011965:Receptors, Glucocorticoid; D018808:Transcription Factor AP-1; D004247:DNA; D048031:JNK Mitogen-Activated Protein Kinases