Related Experiment Video

Updated: Jun 8, 2026

Detection of Inflammasome Activation and Pyroptotic Cell Death in Murine Bone Marrow-derived Macrophages
06:52

Detection of Inflammasome Activation and Pyroptotic Cell Death in Murine Bone Marrow-derived Macrophages

Published on: May 21, 2018

Apoptotic cell-derived factors induce arginase II expression in murine macrophages by activating ERK5/CREB

Vera Barra1, Anne-Marie Kuhn, Andreas von Knethen

  • 1Faculty of Medicine, Institute of Biochemistry I, Goethe University Frankfurt, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany.

Cellular and Molecular Life Sciences : CMLS
|October 16, 2010
PubMed

Insights

Apoptotic cells induce macrophages to become anti-inflammatory by upregulating arginase II (ARG II). This process involves sphingosine-1-phosphate (S1P) signaling through S1P receptor 2 (S1P2), activating ERK5 and CREB pathways.

Area of Science:

  • Immunology
  • Cell Biology
  • Biochemistry

Background:

  • Apoptotic cells (ACs) induce macrophages (MΦs) to adopt an anti-inflammatory phenotype.
  • This phenotype is characterized by reduced nitric oxide (NO) production, partly due to increased arginase II (ARG II) expression.
  • ARG II competes with inducible NO synthase for L-arginine, impairing NO formation.

Purpose of the Study:

  • To elucidate the signaling pathways by which AC-derived factors upregulate ARG II in MΦs.
  • To identify the specific molecules and receptors involved in this regulatory process.

Main Methods:

  • Utilized RAW264.7 MΦs treated with AC-conditioned medium (CM).
  • Investigated the roles of sphingosine-1-phosphate (S1P), S1P receptor 2 (S1P2), ERK5, and CREB using knockdown experiments and Electrophoretic Mobility Shift Assays (EMSA).
  • Employed decoy oligonucleotides to assess CREB involvement.

Main Results:

  • S1P was essential for CM-induced ARG II upregulation, acting synergistically with another factor.
  • S1P activated S1P2, as S1P2 knockdown abrogated ARG II induction.
  • ERK5 and CREB were implicated in the signaling cascade, with their knockdown attenuating ARG II protein levels.
  • EMSA and decoy oligonucleotides confirmed CREB's role in mediating ARG II expression.

Conclusions:

  • AC-derived S1P binds to S1P2, initiating a signaling cascade.
  • This cascade involves synergistic action with other factors to activate ERK5 and CREB.
  • The identified signaling pathway (S1P/S1P2/ERK5/CREB) induces ARG II, promoting an anti-inflammatory MΦ phenotype.

More Related Videos

Experimental Analysis of Apoptotic Thymocyte Engulfment by Macrophages06:47

Experimental Analysis of Apoptotic Thymocyte Engulfment by Macrophages

Published on: May 24, 2019

Identification of Intracellular Signaling Events Induced in Viable Cells by Interaction with Neighboring Cells Undergoing Apoptotic Cell Death09:18

Identification of Intracellular Signaling Events Induced in Viable Cells by Interaction with Neighboring Cells Undergoing Apoptotic Cell Death

Published on: December 27, 2016

Related Concept Videos

The Extrinsic Apoptotic Pathway01:17

The Extrinsic Apoptotic Pathway

The extrinsic apoptotic pathway is initiated when extracellular death-inducing signals, such as specific cytokines, activate the death receptors expressed on the cell surface. The immune cells involved in this pathway are natural killer cells (NK cells) and cytotoxic T-lymphocytes. NK cells are critical in innate immune response, while cytotoxic T-lymphocytes are associated with adaptive immune response. These cells recognize specific receptors expressed on the altered cells and activate...
PI3K/mTOR/AKT Signaling Pathway01:22

PI3K/mTOR/AKT Signaling Pathway

The mammalian target of rapamycin  (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1  (mTORC1) and mTOR complex 2  (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast,  mTORC2 consists of a rapamycin-insensitive companion...
The Intrinsic Apoptotic Pathway01:31

The Intrinsic Apoptotic Pathway

Internal cellular stress, such as cellular injury or hypoxia, triggers intrinsic apoptosis. The B-cell lymphoma 2 (Bcl-2) family of proteins are the primary regulators of the intrinsic apoptotic pathway. For example, during DNA damage, checkpoint proteins, such as Ataxia Telangiectasia Mutated (ATM protein) and Checkpoints Factor-2 (Chk2) proteins, are activated. These proteins phosphorylate p53 which further activates pro-apoptotic proteins, such as Bax, Bak, PUMA, and Noxa, and inhibits...
Phagocytosis of Apoptotic Cells01:17

Phagocytosis of Apoptotic Cells

Cells undergoing apoptosis form apoptotic bodies that must be removed immediately to prevent inflammation, autoimmune diseases, and necrosis. Phagocytosis is carried out by professional phagocytes such as macrophages or  immature dendritic cells. Non-professional phagocytes such as  epithelial cells and fibroblasts also take part in this process; however, they are not as effective as professional phagocytes. 
Normal cells contain receptors that prevent them from being recognized by phagocytes.
Autophagic Cell Death01:18

Autophagic Cell Death

Christian de Duve discovered “autophagy,” a process in which cellular components are engulfed by membrane-bound organelles called autophagosomes. The autophagosomes then fuse with lysosomes to digest the enclosed contents. Autophagy is generally activated in cells to prevent cell death. However, cell death is triggered when the damage is beyond repair.
Autophagy and Apoptosis
Autophagy can activate apoptosis. In normal conditions, the autophagy activating protein Beclin-1 and pro-apoptotic...