Related Experiment Video

Updated: Aug 16, 2026

Measuring Composition of CD95 Death-Inducing Signaling Complex and Processing of Procaspase-8 in this Complex
07:17

Measuring Composition of CD95 Death-Inducing Signaling Complex and Processing of Procaspase-8 in this Complex

Published on: August 2, 2021

Death receptor-induced signaling pathways are differentially regulated by gamma interferon upstream of caspase 8

Daniela Siegmund1, Andreas Wicovsky, Ingo Schmitz

  • 1Department of Molecular Internal Medicine, Medical Polyclinic, University of Würzburg, Röntgenring 11, 97070 Würzburg, Germany.

Molecular and Cellular Biology
|July 19, 2005
PubMed

Insights

Gamma interferon (IFN-gamma) enhances FasL-induced apoptosis and proinflammatory gene activation by sensitizing the death-inducing signaling complex (DISC). This cytokine cross-talk impacts cellular responses beyond simple death receptor signaling.

Area of Science:

  • Immunology
  • Cell Biology
  • Molecular Signaling

Background:

  • Fas ligand (FasL) and gamma interferon (IFN-gamma) are key cytokines produced by immune cells.
  • Both cytokines can induce apoptosis and proinflammatory responses.
  • The cross-talk between FasL and IFN-gamma regarding non-apoptotic signaling is not well understood.

Purpose of the Study:

  • To investigate the non-apoptotic signaling cross-talk between FasL and IFN-gamma.
  • To determine how IFN-gamma influences FasL- and TRAIL-mediated signaling pathways.
  • To elucidate the role of the death-inducing signaling complex (DISC) in this cross-talk.

Main Methods:

  • Utilized KB cells and manipulated apoptosis pathways using caspase inhibitors and Bcl2 overexpression.
  • Assessed apoptosis induction and NF-kappaB activation.
  • Investigated the role of FLIP(L) and FLIP(S) in regulating these responses.
  • Analyzed the activation of signaling molecules like caspase 8, JNK, p38, and p42/44.

Main Results:

  • IFN-gamma sensitizes cells to apoptosis by enhancing DISC-mediated caspase 8 processing.
  • IFN-gamma also sensitizes cells to Fas- and TRAIL-mediated NF-kappaB activation, leading to synergistic upregulation of proinflammatory genes, even when protected from apoptosis.
  • Fas-mediated activation of JNK, p38, and p42/44 was largely independent of IFN-gamma sensitization.
  • Overexpression of FLIP isoforms inhibited both apoptosis and NF-kappaB activation in IFN-gamma-primed cells.

Conclusions:

  • IFN-gamma plays a critical role in sensitizing cells to both apoptosis and non-apoptotic signaling pathways initiated by death receptors like Fas and TRAIL.
  • The cross-talk between FasL and IFN-gamma involves synergistic regulation of NF-kappaB activation and proinflammatory gene expression.
  • These findings suggest that both apoptotic and non-apoptotic responses mediated by the DISC are coregulated by IFN-gamma.

More Related Videos

Evaluation of Caspase Activation to Assess Innate Immune Cell Death10:23

Evaluation of Caspase Activation to Assess Innate Immune Cell Death

Published on: January 20, 2023

Measuring Caspase Activity Using a Fluorometric Assay or Flow Cytometry05:29

Measuring Caspase Activity Using a Fluorometric Assay or Flow Cytometry

Published on: March 24, 2023

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...
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...
Caspases01:24

Caspases

Caspase, a family of cysteine proteases, serve as effectors in apoptosis. The ced3 gene in C.elegans was first identified to be involved in apoptosis. This gene encodes the ced-3 caspase that is similar to the interleukin-1-beta converting enzyme or ICE in mammals. In addition to apoptosis, caspases also function in the inflammatory response. Inflammatory caspases are essential in activating pro-inflammatory cytokines that recruit immune cells and block the replication of pathogens inside cells.
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...
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 the...
Receptor Downregulation in MVBs01:15

Receptor Downregulation in MVBs

Multivesicular bodies (MVBs) are mature endosomes that sort ubiquitinated proteins and then fuse with lysosomes to degrade the sorted proteins. Epidermal growth factor (EGF) and its receptor (EGFR) form a complex that can be internalized through endocytosis, sorted into an MVB, and later degraded.
The EGFR can initiate signaling pathways that  lead to cell proliferation, migration, and differentiation. Overexpression of EGFR  stimulates cells to proliferate. Excessive  EGFR activation may...