Fig. 3

Schematic representation of transcriptomic adaptations and molecular pathways involved in triggering premature mammary involution in gilts that experienced sustained hyperprolactinemia from d 90 to 109 of gestation. Injections of the dopamine receptor antagonist domperidone from d 90 to 109 of gestation provoked sustained hyperprolactinemia. Upon binding to its receptor (PRLR), PRL activates the JAK2-STAT5 signaling pathway, which then induces the transcription of milk proteins such as WAP, CSN1S2 and LALBA. STAT5 can also induce the transcription of AKT and P85, two proteins that are part of the PI3k-AKT signaling pathway. In the absence of milk removal, the JAK1-STAT3 signaling pathway is activated leading to programmed cell death. In the first phase of mammary involution, the lysosomal cell death is mediated through the LIFR-JAK1-STAT3 signaling pathway. In the second phase, oncostatin M and its receptor (OSMR) mediate the apoptotic cell death. The up-regulation of FOXO1 is known to induce cellular apoptosis. The downregulation of PRLR transcript and the increased expression of PTPN6 and CISH suggest a negative feedback loop to reduce the activation of the PRLR-JAK2-STAT5 signaling pathway. The upregulation of PPP2R3A and downregulation of HSP90AB1 may inactivate the PI3K-Akt signaling pathway. The up-regulation of S100A12, LTF, TLR2, TLR4, MYD88, CXCL2, CXCL8 and CCL23 transcripts suggests an activation of the TLR-NF-κB signaling pathway. The up-regulation of CXCL2, CXCL8 and CCL23 chemokines, as well as the IL2, IL6 and TNF receptors may induce the infiltration of neutrophils and professional phagocytes (macrophages) in the involuting mammary glands. Differentially expressed genes are indicated in yellow boxes with up-regulated genes in bold character and down-regulated genes in plain text. AKT: AKT serine/threonine kinase; BIM/BCL2L11: BCL2 like 11; CCL2: C-C motif chemokine ligand 2; CCND1: cyclin D1; CIDEA: cell death inducing DFFA like effector A; CISH: cytokine inducible SH2 containing protein; CSN1S2: alpha(s2)-casein; gp130: glycoprotein 130; CTSC: cathepsin C; CTSH: cathepsin H; CXCL2: C-X-C motif chemokine ligand 2; CXCL8: C-X-C motif chemokine ligand 8; FASL: fas ligand; FOS: Fos proto-oncogene, AP1 transcription factor subunit; FOXO1: forkhead box O1; HSP90AB1: heat shock protein 90 alpha family class B member 1; IKBα: NFKB inhibitor alpha; IKKβ: inhibitor of nuclear factor kappa B kinase subunit beta; IL2: interleukin 2; IL2RG: interleukin 2 receptor subunit gamma; IL6: interleukin 6; IL6R: interleukin 6 receptor; IRAK: interleukin 1 receptor associated kinase; JAK1: janus kinase 1; JAK2, janus kinase 2; LALBA: lactalbumin alpha; LIFR: LIF receptor subunit alpha; LITAF: LPS induced TNF factor; LTF: lactotransferrin; MCL1: MCL1 apoptosis regulator, BCL2 family member; MYC: MYC proto-oncogene, BHLH transcription factor; MYD88: MYD88 innate immune signal transduction adaptor; NEMO/IKBKG: inhibitor of nuclear factor kappa B kinase regulatory subunit gamma; NF-κB: nuclear factor kappa B; OSMR: oncostatin M receptor; P85: phosphoinositide-3-kinase regulatory subunit 1; PI3K: phosphoinositide-3-kinase; PPP2R3A: protein phosphatase 2 regulatory subunit B alpha; PRL: prolactin; PRLR: prolactin receptor; PTPN6: protein tyrosine phosphatase non-receptor type 6; S100A12: S100 calcium binding protein A12; STAT3: signal transducer and activator of transcription 3; STAT5: signal transducer and activator of transcription 5; STING1: stimulator of interferon response CGAMP interactor 1; TAK1/MAP 3 K7: mitogen-activated kinase kinase kinase 7; TIRAP: TIR domain containing adaptor protein; TLR2: toll like receptor 2; TLR4: toll like receptor 4; TNF: tumor necrosis factor; TNFRSF17: TNF receptor superfamily member 17; TRAF6: TNF receptor associated factor 6; WAP: whey acid protein