Comparative study of gp130 cytokine effects on corticotroph AtT-20 cells--redundancy or specificity of neuroimmunoendocrine modulators?
OBJECTIVE
This comparative in vitro study examined the effects of all known gp130 cytokines on murine corticotroph AtT-20 cell function.


METHODS
Cytokines were tested at equimolar concentrations from 0.078 to 10 nM. Tyrosine phosphorylation of the signal transducer and activator of transcription (STAT)3 and STAT1, the STAT-dependent suppressor of cytokine signaling (SOCS)-3 promoter activity, SOCS-3 gene expression, STAT-dependent POMC promoter activity and adrenocorticotropic hormone (ACTH) secretion were determined.


RESULTS
Leukemia inhibitory factor (LIF), human oncostatin M (OSM) and cardiotrophin (CT)-1 (LIFR/gp130 ligands), as well as ciliary neurotrophic factor (CNTF) and novel neurotrophin-1/B-cell stimulating factor-3 (CNTFR alpha/LIFR/gp130 ligands) are potent stimuli of corticotroph cells in vitro. In comparison, interleukin (IL)-6 (IL-6R/gp130 ligand) and IL-11 (IL-11R/gp130 ligand) exhibited only modest direct effects on corticotrophs, while murine OSM (OSMR/gp130 ligand) showed no effect.


CONCLUSIONS
(i) CNTFR complex ligands are potent stimuli of corticotroph function, comparable to LIFR complex ligands; (ii) IL-6 and IL-11 are relatively weak direct stimuli of corticotroph function; (iii) differential effects of human and murine OSM suggest that LIFR/gp130 (OSMR type I) but not OSMR/gp130 (OSMR type II) are involved in corticotroph signaling. (iv) CT-1 has the hitherto unknown ability to stimulate corticotroph function, and (v) despite redundant immuno-neuroendocrine effects of different gp130 cytokines, corticotroph cells are preferably activated through the LIFR and CNTFR complexes.
Auernhammer
Christoph J
CJ
Medizinische Klinik II, Klinikum Grosshadern, Ludwig-Maximilians-Universität, Munich, Germany. Christoph.Auernhammer@med2.med.uni-muenchen.de
Kopp
Florian B
FB
Vlotides
George
G
Dorn
Franziska
F
Isele
Nicola B
NB
Spöttl
Gerald
G
Cengic
Neziha
N
Weber
Matthias M
MM
Senaldi
Giorgio
G
Engelhardt
Dieter
D
D000324:Adrenocorticotropic Hormone / Q000378:metabolism; D000818:Animals; D015703:Antigens, CD / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D002460:Cell Line; D050822:Cytokine Receptor gp130; D016207:Cytokines / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression / Q000187:drug effects / Q000276:immunology; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects / Q000276:immunology*; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit; D008024:Ligands; D008562:Membrane Glycoproteins / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D015213:Neuroimmunomodulation / Q000276:immunology*; D010766:Phosphorylation / Q000187:drug effects; D010903:Pituitary Gland, Anterior / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D011333:Pro-Opiomelanocortin / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000276:immunology; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D020801:Receptor, Ciliary Neurotrophic Factor / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D018121:Receptors, Cytokine / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D053606:Receptors, OSM-LIF; D012097:Repressor Proteins / Q000235:genetics; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics; D014443:Tyrosine / Q000378:metabolism
D015703:Antigens, CD; D016207:Cytokines; D004268:DNA-Binding Proteins; C494200:Il6st protein, mouse; C507840:LIFR protein, human; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit; C507841:Lifr protein, mouse; D008024:Ligands; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D020801:Receptor, Ciliary Neurotrophic Factor; D018121:Receptors, Cytokine; D053606:Receptors, OSM-LIF; D012097:Repressor Proteins; C106644:SOCS3 protein, human; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; C491411:Socs3 protein, mouse; C494080:Stat1 protein, mouse; C494087:Stat3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D050822:Cytokine Receptor gp130; D014443:Tyrosine; D011333:Pro-Opiomelanocortin; D000324:Adrenocorticotropic Hormone