Interferon-Tau Exerts Direct Prosurvival and Antiapoptotic Actions in Luteinized Bovine Granulosa Cells

Abstract

Interferon-tau (IFNT), serves as a signal to maintain the corpus luteum (CL) during early pregnancy in domestic ruminants. We investigated here whether IFNT directly affects the function of luteinized bovine granulosa cells (LGCs), a model for large-luteal cells. Recombinant ovine IFNT (roIFNT) induced the IFN-stimulated genes (ISGs; MX2, ISG15, and OAS1Y). IFNT induced a rapid and transient (15–45 min) phosphorylation of STAT1, while total STAT1 protein was higher only after 24 h. IFNT treatment elevated viable LGCs numbers and decreased dead/apoptotic cell counts. Consistent with these effects on cell viability, IFNT upregulated cell survival proteins (MCL1, BCL-xL, and XIAP) and reduced the levels of gamma-H2AX, cleaved caspase-3, and thrombospondin-2 (THBS2) implicated in apoptosis. Notably, IFNT reversed the actions of THBS1 on cell viability, XIAP, and cleaved caspase-3. Furthermore, roIFNT stimulated proangiogenic genes, including FGF2, PDGFB, and PDGFAR. Corroborating the in vitro observations, CL collected from day 18 pregnant cows comprised higher ISGs together with elevated FGF2, PDGFB, and XIAP, compared with CL derived from day 18 cyclic cows. This study reveals that IFNT activates diverse pathways in LGCs, promoting survival and blood vessel stabilization while suppressing cell death signals. These mechanisms might contribute to CL maintenance during early pregnancy.

Downregulated luteolytic pathways in the transcriptome of early pregnancy bovine corpus luteum are mimicked by interferon-tau in vitro

“…Furthermore, intraluteal and circulating progesterone levels as well as CL volume were maintained, and these CL had a greater expression of genes for cell survival [ 26 ]. Our in vitro data, which show the effects of IFNT on luteal cells [ 16 , 17 , 27 ], further support a direct role of IFNT on luteal function.…”

“…4 B). Some of these ISGs ( IRF9 , ISG15 , MX2, and OAS1 ) were previously shown to be significantly elevated by in vitro treatment of roIFNT in bovine CL tissue, luteal endothelial cells, and LGCs [ 16 , 17 ] (Insert table Fig. 4 B).…”

“…Another factor that may take part in vascular maturation is PDGFB, which attracts pericytes, thus stabilizing blood vessels [ 55 ]. This study demonstrated that PDGFB is upregulated in the CL of P cows and is stimulated by roIFNT in LGCs in vitro [ 17 ]. Corroborating this notion, in bovine luteal endothelial cell network established in vitro, the inhibition of PDGF signaling markedly decreased its formation and sprouting [ 56 ].…”

“…Antiapoptotic proteins such as BCL-2, MCL-1, and BCL-XL were shown to be GLI target genes [ 18 ]. These proteins were increased in CL by IFNT in vivo [ 15 ] and in LGCs in vitro [ 17 ]. Interestingly, we found here that IFNT elevated GLI2 and PTCH2 mRNA expression but not GLI1 and SUFU in LGCs.…”

“…Nevertheless, in addition to its uterine actions, an endocrine role for IFNT has been suggested [ 9 , 23 ]. Antiviral activity was detected in uterine vein blood [ 14 , 24 ] and ISGs were expressed in CL from pregnant ruminants as well as during uterine vein infusion of recombinant ovine IFNT (roIFNT) [ 14 , 17 , 18 , 25 ]. Notably, endocrine delivery of roIFNT, via the uterine or jugular vein, protected the ovine CL from the luteolytic actions of PGF2A [ 26 ].…”