Modulation of matrix metalloproteases by ciliary neurotrophic factor in human placental development.

Giovanni Tossetta, Sonia Fantone, Elena Marinelli Busilacchi, Nicoletta Di Simone, Stefano R Giannubilo, Giovanni Scambia, Antonio Giordano, Daniela Marzioni

Journal: Cell and tissue research 2022;390(1):113-129

PMID: 35794391

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Abstract

Ciliary neurotrophic factor (CNTF) is a pleiotropic cytokine that signals through a receptor complex containing a specific subunit, CNTF receptor α (CNTFRα). The two molecules are constitutively expressed in key structures for human placental growth and differentiation. The possible role of CNTF in enhancing cell proliferation and/or invasion during placental development and remodelling was investigated using HTR-8/SVneo and BeWo cells, taken respectively as cytotrophoblast and syncytiotrophoblast models. In both cell lines, treatment with human recombinant (hr) CNTF activated JAK2/STAT3 signalling and inhibited the ERK pathway. Interestingly, in HTR-8/SVneo cells, 50 ng hrCNTF induced significant downregulation of matrix metalloprotease (MMP)-1 and significant upregulation of MMP-9. Moreover, pharmacological inhibition of JAK2/STAT3 signalling by AG490 and curcumin resulted in MMP-9 downregulation; it activated the ERK signalling pathway and upregulated MMP-1 expression. Collectively, these data suggest a role for CNTF signalling in extravillous cytotrophoblast invasion through the modulation of specific MMPs.

Address: Department of Experimental and Clinical Medicine, Università Politecnica Delle Marche, 60126, Ancona, Italy.; Clinica Di Ostetricia E Ginecologia, Azienda Ospedaliero Universitaria Ospedali Riuniti Di Ancona, 60123, Ancona, Italy.; Department of Clinical and Molecular Sciences, Università Politecnica Delle Marche, Ancona, Italy.; Hematology Unit, AUO Ospedali Riuniti Di Ancona, 60123, Ancona, Italy.; Department of Biomedical Science, Humanitas University, Via Rita Levi Montalcini 4, 20090, Pieve Emanuele, Milan, Italy.; Humanitas Clinical and Research Center-IRCCS, Via Manzoni56, 20089, Rozzano, Italy.; Department of Clinical Sciences, Università Politecnica Delle Marche, Salesi Hospital, 60123, Ancona, Italy.; U.O.C. Di Ostetricia E Patologia Ostetrica, Dipartimento Di Scienze Della Salute Della Donna, Fondazione Policlinico Universitario A. Gemelli IRCCS, del Bambino E Di Sanità Pubblica, 00168, Rome, Italy.; Istituto Di Clinica Ostetrica E Ginecologica, Università Cattolica del Sacro Cuore, 00168, Rome, Italy.; Department of Experimental and Clinical Medicine, Università Politecnica Delle Marche, 60126, Ancona, Italy. [email protected].; Department of Experimental and Clinical Medicine, Università Politecnica Delle Marche, 60126, Ancona, Italy. [email protected].

DOI: 10.1007/s00441-022-03658-1

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MeSH Terms: Ciliary Neurotrophic Factor, Ciliary Neurotrophic Factor Receptor alpha Subunit, Curcumin, Cytokines, Female, Humans, Matrix Metalloproteinase 1, Matrix Metalloproteinase 9, Placenta, Placentation, Pregnancy, Receptor, Ciliary Neurotrophic Factor