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An antagonist for the leukemia inhibitory factor receptor inhibits leukemia inhibitory factor, cardiotrophin-1,
A B Vernallis1, K R Hudson, J K Heath
1CRC Growth Factor Group, School of Biochemistry, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom.
Abstract:
The leukemia inhibitory factor receptor (LIF-R) is activated not only by LIF, but also by cardiotrophin-1, ciliary neurotrophic factor with its receptor, and oncostatin M (OSM). Each of these cytokines induces the hetero-oligomerization of LIF-R with gp130, a signal-transducing subunit shared with interleukin-6 and interleukin-11. The introduction of mutations into human LIF that reduced the affinity for gp130 while retaining affinity for LIF-R has generated antagonists for LIF. In the current study, a LIF antagonist that was free of detectable agonistic activity was tested for antagonism against the family of LIF-R ligands. On cells that express LIF-R and gp130, all LIF-R ligands were antagonized. On cells that also express OSM receptor, OSM was not antagonized, demonstrating that the antagonist is specific for LIF-R. Ligand-triggered tyrosine phosphorylation of both LIF-R and gp130 was blocked by the antagonist. The antagonist is therefore likely to work by preventing receptor oligomerization.
Insights
A novel leukemia inhibitory factor (LIF) antagonist specifically blocks LIF receptor (LIF-R) signaling by preventing receptor complex formation. This discovery offers new therapeutic strategies for LIF-R-mediated diseases.
Area of Science:
- Molecular and Cellular Biology
- Receptor Signaling Pathways
- Cytokine Receptor Interactions
Background:
- Leukemia inhibitory factor receptor (LIF-R) mediates cellular responses through interactions with various cytokines, including LIF, cardiotrophin-1, ciliary neurotrophic factor, and oncostatin M (OSM).
- Cytokine binding induces hetero-oligomerization of LIF-R with the shared signal-transducing subunit gp130, a process critical for downstream signaling.
- Previous research has generated LIF antagonists by modifying LIF to reduce gp130 affinity while maintaining LIF-R binding.
Purpose of the Study:
- To evaluate a novel, pure LIF antagonist for its ability to inhibit signaling mediated by the broader family of LIF-R ligands.
- To determine the specificity of the LIF antagonist against different LIF-R-activating cytokines.
- To elucidate the mechanism of action of the LIF antagonist in blocking receptor-mediated signaling.
Main Methods:
- A purified LIF antagonist, lacking agonistic activity, was tested against various LIF-R ligands on cells expressing LIF-R and gp130.
- Specificity was assessed on cells co-expressing the oncostatin M receptor (OSMR).
- Tyrosine phosphorylation of LIF-R and gp130 upon ligand stimulation was analyzed in the presence and absence of the antagonist.
Main Results:
- The LIF antagonist effectively inhibited all tested LIF-R ligands on cells expressing LIF-R and gp130.
- Oncostatin M signaling remained unaffected on cells co-expressing OSMR, confirming the antagonist's specificity for LIF-R.
- Ligand-induced tyrosine phosphorylation of both LIF-R and gp130 was abrogated by the antagonist.
Conclusions:
- The developed LIF antagonist specifically inhibits LIF-R signaling across multiple ligands.
- The antagonist functions by preventing the crucial hetero-oligomerization of LIF-R with gp130, thereby blocking signal transduction.
- This antagonist represents a valuable tool for dissecting LIF-R signaling pathways and holds potential for therapeutic applications.