Interleukin 11 signaling components signal transducer and activator of transcription 3 (STAT3) and suppressor of cytokine signaling 3 (SOCS3) regulate human endometrial stromal cell differentiation.
The differentiation of endometrial stromal cells into decidual cells (decidualization) is critical for embryo implantation, but the mechanisms remain poorly defined. Numerous paracrine agents including IL-11 promote human endometrial stromal cell (HESC) decidualization. IL-11 signaling is transduced by the signal transducers and activators of transcription (STAT) proteins. Suppressors of cytokine signaling (SOCS) proteins are stimulated in response to cytokine-inducible STAT phosphorylation, acting in a negative-feedback mechanism to hinder cytokine receptor activity. This study examined the role of IL-11 signal transduction components in HESC decidualization in an ex vivo model. Cells were induced to differentiate with estrogen plus medroxyprogesterone acetate (E+P) or cAMP (assessed by prolactin secretion) and resulted in increased STAT3 and SOCS3. E+P maximally stimulated STAT3, whereas cAMP maximally stimulated SOCS3 during decidualization, suggesting E+P and cAMP differentially regulated the signaling components. IL-11 stimulated the phosphorylation (p) of STAT3 and SOCS3 mRNA and protein. Antiprogestin (onapristone) added to decidualizing cells attenuated STAT3 protein but increased SOCS3 mRNA and protein, suggesting regulation via both ligand-dependent and -independent progesterone-receptor pathways. SOCS3 overexpression in HESC reduced IL-11-induced pSTAT3 and retarded decidualization, indicating that SOCS3 is a critical regulator of differentiation. Immunoreactive pSTAT3 and SOCS3 were all present in decidualized stromal cells, epithelial cells, and leukocytes in human endometrium. These data support a role for IL-11 via pSTAT3 and SOCS3 in initiating and progressing decidualization.
Dimitriadis
Evdokia
E
Prince Henry's Institute of Medical Research, Victoria 3168, Australia. evdokia.dimitriadis@princehenrys.org
Stoikos
Chelsea
C
Tan
Yee-Lee
YL
Salamonsen
Lois A
LA
D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D003656:Decidua / Q000166:cytology / Q000378:metabolism; D004717:Endometrium / Q000166:cytology* / Q000378:metabolism; D005260:Female; D015870:Gene Expression / Q000502:physiology; D006801:Humans; D007150:Immunohistochemistry; D017370:Interleukin-11 / Q000378:metabolism*; D008597:Menstrual Cycle / Q000502:physiology; D011374:Progesterone / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D017154:Stromal Cells / Q000166:cytology* / Q000378:metabolism; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism*
C508611:IL11 protein, human; D017370:Interleukin-11; D012333:RNA, Messenger; C106644:SOCS3 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D011374:Progesterone; D000242:Cyclic AMP