NOD2 receptors in adenopituitary folliculostellate cells: expression and function.
Folliculostellate cells (FS cells) are non-endocrine cells from the pituitary gland that respond to bacterial endotoxins by producing cytokines. In immune cells, an important component of bacterial recognition are the toll-like receptors (TLRs). Previously, we showed that FS cells express TLR4. The TLR4 ligand lipopolysaccharide (LPS) stimulates interleukin-6 (IL6) production through nuclear factor kappaB (NFKB) induction. Binding of IL6 to gp130 receptor activates signal transducer and activator of transcription 3 (STAT3), an important mediator of inflammatory response. Another family involved in innate immune response following bacterial infection is the nucleotide-binding oligomerisation domain (NOD) intracellular receptor family. Herein, we describe for the first time the expression and function of NOD receptors in human pituitary and FS TtT/GF cell line. The NOD2 agonist muramyl dipeptide (MDP) increased Nf kappa b1-transcriptional activity, -protein expression and IL6 secretion in TtT/GF cells. Furthermore, these effects were potentiated by the combination of MDP and LPS. Silencing NOD2 abolished the action of LPS on NFKB transcriptional activity and IL6 production, indicating that, in TtT/GF cells, TLR4 transduces its signal through NOD2 receptor. We show here that in TtT/GF cells, Nod2 overexpression or stimulation by MDP increased STAT3 transcriptional activity. Furthermore, silencing STAT3 inhibited basal, LPS and MDP stimulated NFKB protein expression and overexpression of protein inhibitor of activated STAT3 (Pias3) markedly decreased basal NFKB activity. These data suggest that in TtT/GF cells, STAT3 acting upstream to NFKB mediates NOD2 receptor signalling pathway. In conclusion, the present study demonstrates that NOD molecules play a modulatory role in the pituitary by regulating the function and activation of FS cells in response to bacterial components.
Correa-de-Santana
Eliane
E
Department of Endocrinology, Max Planck Institute of Psychiatry, Kraepelinstrasse 2-10, 80804 Munich, Germany. santana@mpipsykl.mpg.de
Fröhlich
Bianca
B
Labeur
Marta
M
Páez-Pereda
Marcelo
M
Theodoropoulou
Marily
M
Monteserin
Jose Luis
JL
Renner
Ulrich
U
Stalla
Günter K
GK
D000119:Acetylmuramyl-Alanyl-Isoglutamine; D000818:Animals; D002460:Cell Line; D005260:Female; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D008070:Lipopolysaccharides; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D053474:Nod1 Signaling Adaptor Protein / Q000378:metabolism; D053473:Nod2 Signaling Adaptor Protein / Q000378:metabolism*; D010902:Pituitary Gland / Q000276:immunology / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D051381:Rats; D017207:Rats, Sprague-Dawley; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
D015850:Interleukin-6; D008070:Lipopolysaccharides; D016328:NF-kappa B; C429018:NOD2 protein, human; D053474:Nod1 Signaling Adaptor Protein; D053473:Nod2 Signaling Adaptor Protein; D050796:STAT3 Transcription Factor; D051197:Toll-Like Receptor 4; D000119:Acetylmuramyl-Alanyl-Isoglutamine