PMID- 32082070 OWN - NLM STAT- MEDLINE DCOM- 20200706 LR - 20200706 IS - 1466-1861 (Electronic) IS - 0962-9351 (Print) IS - 0962-9351 (Linking) VI - 2019 DP - 2019 TI - Amphiregulin Regulates Phagocytosis-Induced Cell Death in Monocytes via EGFR and the Bcl-2 Protein Family. PG - 1603131 LID - 10.1155/2019/1603131 [doi] LID - 1603131 AB - Neonates are extremely susceptible to bacterial infections, and evidences suggest that phagocytosis-induced cell death (PICD) is less frequently triggered in neonatal monocytes than in monocytes from adult donors. An insufficient termination of the inflammatory response, leading to a prolonged survival of neonatal monocytes with ongoing proinflammatory cytokine release, could be associated with the progression of various inflammatory diseases in neonates. Our previous data indicate that amphiregulin (AREG) is increasingly expressed on the cell surface of neonatal monocytes, resulting in remarkably higher soluble AREG levels after proteolytic shedding. In this study, we found that E. coli-infected neonatal monocytes show an increased phosphorylation of ERK, increased expression of Bcl-2 and Bcl-X(L), and reduced levels of cleaved caspase-3 and caspase-9 compared to adult monocytes. In both cell types, additional stimulation with soluble AREG further increased ERK activation and expression of Bcl-2 and Bcl-X(L) and reduced levels of cleaved caspase-3 and caspase-9 in an EGFR-dependent manner. These data suggest that reduced PICD of neonatal monocytes could be due to reduced intrinsic apoptosis and that AREG can promote protection against PICD. This reduction of the intrinsic apoptosis pathway in neonatal monocytes could be relevant for severely prolonged inflammatory responses of neonates. CI - Copyright (c) 2019 Christopher Platen et al. FAU - Platen, Christopher AU - Platen C AUID- ORCID: 0000-0003-4063-7789 AD - Department of Neonatology, University Children's Hospital, Aachen, Germany. FAU - Dreschers, Stephan AU - Dreschers S AUID- ORCID: 0000-0003-2527-3673 AD - Department of Neonatology, University Children's Hospital, Aachen, Germany. FAU - Wappler, Jessica AU - Wappler J AUID- ORCID: 0000-0003-1431-9613 AD - Molecular Tumor Biology, Department of General, Visceral and Transplantation Surgery, University Hospital, Aachen, Germany. FAU - Ludwig, Andreas AU - Ludwig A AUID- ORCID: 0000-0001-8536-4986 AD - Institute of Pharmacology and Toxicology, Medical Faculty, RWTH Aachen University, Aachen, Germany. FAU - Dusterhoft, Stefan AU - Dusterhoft S AD - Institute of Pharmacology and Toxicology, Medical Faculty, RWTH Aachen University, Aachen, Germany. FAU - Reiss, Lucy Kathleen AU - Reiss LK AUID- ORCID: 0000-0001-9567-3328 AD - Institute of Pharmacology and Toxicology, Medical Faculty, RWTH Aachen University, Aachen, Germany. FAU - Orlikowsky, Thorsten W AU - Orlikowsky TW AUID- ORCID: 0000-0001-7123-0629 AD - Department of Neonatology, University Children's Hospital, Aachen, Germany. LA - eng PT - Journal Article DEP - 20191103 PL - United States TA - Mediators Inflamm JT - Mediators of inflammation JID - 9209001 RN - 0 (Amphiregulin) RN - 0 (Interleukin-6) RN - 0 (Proto-Oncogene Proteins c-bcl-2) RN - 9007-41-4 (C-Reactive Protein) RN - 9007-43-6 (Cytochromes c) RN - EC 2.7.10.1 (EGFR protein, human) RN - EC 2.7.10.1 (ErbB Receptors) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 3.4.22.- (Caspase 3) RN - EC 3.4.22.- (Caspase 9) SB - IM MH - Amphiregulin/*pharmacology MH - C-Reactive Protein/metabolism MH - Caspase 3/metabolism MH - Caspase 9/metabolism MH - Cell Death/drug effects MH - Cytochromes c/metabolism MH - ErbB Receptors/genetics/metabolism MH - Flow Cytometry MH - Humans MH - Interleukin-6/metabolism MH - Leukocytes, Mononuclear/drug effects/metabolism MH - Phagocytosis/*drug effects/physiology MH - Phosphorylation/drug effects/genetics MH - Proto-Oncogene Proteins c-akt/genetics/*metabolism MH - Proto-Oncogene Proteins c-bcl-2/genetics/*metabolism PMC - PMC7012211 COIS- The authors declare that they have no conflicts of interest. EDAT- 2020/02/23 06:00 MHDA- 2020/07/07 06:00 PMCR- 2019/11/03 CRDT- 2020/02/22 06:00 PHST- 2019/04/16 00:00 [received] PHST- 2019/08/08 00:00 [revised] PHST- 2019/08/26 00:00 [accepted] PHST- 2020/02/22 06:00 [entrez] PHST- 2020/02/23 06:00 [pubmed] PHST- 2020/07/07 06:00 [medline] PHST- 2019/11/03 00:00 [pmc-release] AID - 10.1155/2019/1603131 [doi] PST - epublish SO - Mediators Inflamm. 2019 Nov 3;2019:1603131. doi: 10.1155/2019/1603131. eCollection 2019.