Related Experiment Video

Updated: Mar 6, 2026

Myeloid Innate Signaling Pathway Regulation by MALT1 Paracaspase Activity
07:09

Myeloid Innate Signaling Pathway Regulation by MALT1 Paracaspase Activity

Published on: January 7, 2019

8.0K

Meprin Metalloproteases Generate Biologically Active Soluble Interleukin-6 Receptor to Induce Trans-Signaling

Philipp Arnold1, Inga Boll2, Michelle Rothaug2

  • 1Institute of Anatomy, University of Kiel, 24118 Kiel, Germany.

Scientific Reports
|March 10, 2017
PubMed

Insights

Meprin enzymes shed Interleukin-6 receptor (IL-6R), creating soluble IL-6R that drives inflammation. This newly identified pathway offers therapeutic targets for inflammatory diseases like arthritis.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Immunology

Background:

  • Soluble Interleukin-6 receptor (sIL-6R) trans-signaling promotes inflammation in conditions like arthritis and neurodegeneration.
  • A Disintegrin And Metalloprotease (ADAM) 10 and 17 mediate IL-6R shedding, but cannot account for all sIL-6R production.

Purpose of the Study:

  • To investigate novel proteases involved in Interleukin-6 receptor (IL-6R) shedding.
  • To characterize the mechanism and functional consequences of IL-6R shedding by meprin enzymes.

Main Methods:

  • Protease assays using recombinant meprin α and β.
  • Analysis of IL-6R cleavage site using mass spectrometry.
  • Correlation studies of meprin β expression and IL-6R levels in human granulocytes.

Main Results:

  • Soluble meprin α and membrane-bound meprin β cleave IL-6R, generating bioactive sIL-6R.
  • Cleavage occurs in the IL-6R stalk region, distinct from ADAM10/17 sites.
  • Soluble meprin β does not shed IL-6R, suggesting a regulatory role.
  • In vivo, meprin β expression negatively correlates with IL-6R levels on granulocytes.

Conclusions:

  • Meprin α and β are novel proteases responsible for shedding IL-6R.
  • This meprin-mediated shedding pathway contributes to IL-6 trans-signaling and inflammation.
  • The findings reveal a new regulatory mechanism for IL-6 trans-signaling with potential therapeutic implications.

More Related Videos

Studying TGF-β Signaling and TGF-β-induced Epithelial-to-mesenchymal Transition in Breast Cancer and Normal Cells06:54

Studying TGF-β Signaling and TGF-β-induced Epithelial-to-mesenchymal Transition in Breast Cancer and Normal Cells

Published on: October 27, 2020

14.6K
Isolation Protocol of Mouse Monocyte-derived Dendritic Cells and Their Subsequent In Vitro Activation with Tumor Immune Complexes11:48

Isolation Protocol of Mouse Monocyte-derived Dendritic Cells and Their Subsequent In Vitro Activation with Tumor Immune Complexes

Published on: May 31, 2018

12.2K

Related Concept Videos

The JAK-STAT Signaling Pathway01:20

The JAK-STAT Signaling Pathway

Several cytokine receptors have tightly bound Janus kinase or JAK proteins attached at their cytosolic tail. Small signaling molecules such as cytokines, growth hormones, or prolactins bind to the cytokine receptors and initiate their dimerization. The dimerization brings the cytosolic JAKs together that trans-phosphorylate and activates each other. The activated JAKs now phosphorylate cytosolic tails of the cytokine receptors, which serve as binding sites for adaptor proteins such as  SH2...
13.5K
TGF - β Signaling Pathway01:16

TGF - β Signaling Pathway

The TGF-β signaling pathway regulates cell growth, differentiation, adhesion, motility, and development. TGF-β ligands that induce TGF-β signaling are synthesized in their latent form. Several proteases or cell surface receptors such as integrins act upon the latent form, releasing the active ligand. There are three types of mammalian TGF-βs: (TGF-β1, TGF-β2, and TGF-β3) that bind as homodimers or heterodimers to TGF-β receptors. The TGF-β receptors...
10.8K
Amplifying Signals via Enzymatic Cascade01:22

Amplifying Signals via Enzymatic Cascade

When a ligand binds to a cell-surface receptor, the receptor's intracellular domain changes shape, which may either activate its enzyme function or allow its binding to other molecules. The initial signal is amplified by most signal transduction pathways. This means that a single ligand molecule can activate multiple molecules of a downstream target. Proteins that relay a signal are most commonly phosphorylated at one or more sites, activating or inactivating the protein. Kinases catalyze...
18.9K
Interactions Between Signaling Pathways01:19

Interactions Between Signaling Pathways

Signaling cascades usually lack linearity. Multiple pathways interact and regulate one another, allowing cells to integrate and respond to diverse environmental stimuli.
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
7.6K
IP3/DAG Signaling Pathway01:11

IP3/DAG Signaling Pathway

Membrane lipids such as phosphatidylinositol (PI) are precursors for several membrane-bound and soluble second messengers. Specific kinases phosphorylate PI and produce phosphorylated inositol phospholipids. One such inositol phospholipids are the  phosphatidylinositol-4,5 bisphosphate [PI(4,5)P2], present in the inner half of the lipid bilayer. Upon ligand binding, GPCR stimulates Gq proteins to turn on phospholipase Cꞵ. Activated phospholipase Cꞵ cleaves PI(4,5)P2 and...
15.4K
MAPK Signaling Cascades01:07

MAPK Signaling Cascades

Mitogen-activated protein kinase, or MAPK pathway, activates three sequential kinases to regulate cellular responses such as proliferation, differentiation, survival, and apoptosis. The canonical MAPK pathway starts with a mitogen or growth factor binding to an RTK. The activated RTKs stimulate Ras, which recruits Raf or MAP3 Kinase (MAPKKK), the first kinase of the MAPK signaling cascade. Raf further phosphorylates and activates MEK or MAP2 Kinases (MAPKK), which in turn phosphorylates MAP...
8.9K