Details for: LIF

Gene ID: 3976

Gene Type:  Protein-coding  - A gene that serves as a template for producing a messenger RNA (mRNA) molecule, which is then translated into a functional protein.

Symbol: LIF

Ensembl ID: ENSG00000128342

Description: LIF interleukin 6 family cytokine

Selected Context(s):  Overall

Cell Significance Landscape

Contexts:

Associated with

Significant Cells

Cell Significance Index (CSI) scores for the chosen context(s)

  • fibroblast of lung CL0002553
    CSI 5.69
    rCSI 5.3%
    PRS 98.43
  • endothelial cell of lymphatic vessel CL0002138
    CSI 4.14
    rCSI 8.21%
    PRS 97.3
  • epithelial cell of lower respiratory tract CL0002632
    CSI 3.9
    rCSI 3.03%
    PRS 98.65
  • skin fibroblast CL0002620
    CSI 3.74
    rCSI 3.23%
    PRS 97.59
  • group 3 innate lymphoid cell CL0001071
    CSI 3.69
    rCSI 2.77%
    PRS 98.4
  • respiratory suprabasal cell CL4033048
    CSI 3.6
    rCSI 4.62%
    PRS 98.01
  • epithelial cell CL0000066
    CSI 3.41
    rCSI 5.25%
    PRS 90.66
  • perivascular cell CL4033054
    CSI 3.35
    rCSI 4.58%
    PRS 98.71
  • pericyte CL0000669
    CSI 3.19
    rCSI 8.49%
    PRS 81.96
  • pancreatic ductal cell CL0002079
    CSI 2.91
    rCSI 5.66%
    PRS 97.51
  • stem cell CL0000034
    CSI 2.88
    rCSI 2.78%
    PRS 96.51
  • luminal epithelial cell of mammary gland CL0002326
    CSI 2.8
    rCSI 5.09%
    PRS 98.6
  • granulocyte CL0000094
    CSI 2.6
    rCSI 3.97%
    PRS 98.57
  • chondrocyte CL0000138
    CSI 2.57
    rCSI 4.09%
    PRS 95.68
  • pancreatic stellate cell CL0002410
    CSI 2.54
    rCSI 14.79%
    PRS 97.82
  • vascular associated smooth muscle cell CL0000359
    CSI 2.42
    rCSI 7.85%
    PRS 97.38
  • basophil CL0000767
    CSI 1.8
    rCSI 3.8%
    PRS 98.39
  • basal cell CL0000646
    CSI 1.72
    rCSI 2.3%
    PRS 96.24
  • kidney loop of Henle thin ascending limb epithelial cell CL1001107
    CSI 1.69
    rCSI 4.37%
    PRS 96.74
  • smooth muscle cell of prostate CL1000487
    CSI 1.3
    rCSI 7.65%
    PRS 98.72
  • group 2 innate lymphoid cell CL0001069
    CSI 0.56
    rCSI 3.05%
    PRS 99.12

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this specific cell.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.
Network Configuration

Explore relationships of the current gene. Select an Interaction Source: 'ONTOLOGY' for shared pathways (GO/Reactome) or 'STRING' for protein-protein interactions. Further refine by selecting context genes and comparing Cell Significance Index (CSI) scores between baseline and target cell types and their specific contexts.

Comma-separated if multiple.
Comma-separated if multiple.
Legend:
  • Query Gene
  • Node Color (Target Cell CSI, relative to current network):
    • Very High
    • High
    • Medium
    • Low
    • Very Low
    • CSI N/A
  • Node Size: Proportional to Target Cell CSI magnitude
  • STRING PPI Edge
  • Shared Pathway Edge (ONTOLOGY)

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Other Information

This section provides additional information about the gene, including a description generated by an AI language model and details about associated proteins.

## Summary Leukemia inhibitory factor ([LIF](/details-gene/3976)) is a pleiotropic, protein-coding gene located on chromosome 22q12.2 that encodes a cytokine belonging to the interleukin-6 (IL-6) family. As a secreted signaling molecule, [LIF](/details-gene/3976) exerts diverse biological effects through its receptor, primarily activating STAT signaling pathways. Its functions are highly context-dependent, encompassing critical roles in embryonic development, such as [embryo implantation](/details-gene/3976) ([GO:0007566](https://www.ebi.ac.uk/QuickGO/term/GO:0007566)), the regulation of [stem cell differentiation](/details-gene/3976) ([GO:0048863](https://www.ebi.ac.uk/QuickGO/term/GO:0048863)), and the modulation of the [immune response](/details-gene/3976) ([GO:0006955](https://www.ebi.ac.uk/QuickGO/term/GO:0006955)). **Overall**, expression data indicates that [LIF](/details-gene/3976) is most significantly expressed in stromal and structural cell types, including [fibroblast of lung](/details-cell/CL0002553), [endothelial cell of lymphatic vessel](/details-cell/CL0002138), and various [epithelial cell](/details-cell/CL0000066) populations, highlighting its central role in tissue homeostasis and repair. A clinical association with this gene has been noted ([159540](https://omim.org/entry/159540)). ## Cellular Roles and Expression Landscape The expression profile of [LIF](/details-gene/3976) underscores its function as a key signaling molecule produced primarily by mesenchymal and stromal cell populations. **Overall**, the highest significance score for [LIF](/details-gene/3976) expression is observed in [fibroblast of lung](/details-cell/CL0002553) (CSI: 5.69), with similarly high significance in [skin fibroblast](/details-cell/CL0002620). This is complemented by strong expression in other structural and vascular-associated cells, such as [endothelial cell of lymphatic vessel](/details-cell/CL0002138), [perivascular cell](/details-cell/CL4033054), and [pericyte](/details-cell/CL0000669). This pattern suggests a fundamental role for [LIF](/details-gene/3976) in maintaining the tissue microenvironment, including angiogenesis and tissue remodeling. Beyond its stromal signature, [LIF](/details-gene/3976) also shows significant expression in several [epithelial cell](/details-cell/CL0000066) types, including [epithelial cell of lower respiratory tract](/details-cell/CL0002632) and [pancreatic ductal cell](/details-cell/CL0002079). Notably, [LIF](/details-gene/3976) is also a significant marker for [group 3 innate lymphoid cell](/details-cell/CL0001071), indicating a specialized role in mucosal immunity. Its expression in [stem cell](/details-cell/CL0000034) populations is consistent with its well-documented function in maintaining pluripotency and regulating differentiation. The collective expression landscape paints a picture of [LIF](/details-gene/3976) as a cytokine that mediates crosstalk between stromal, epithelial, and immune compartments to coordinate tissue development, homeostasis, and response to injury. ## Pathways and Molecular Function [LIF](/details-gene/3976) functions as a cytokine ([GO:0005125](https://www.ebi.ac.uk/QuickGO/term/GO:0005125)) and growth factor ([GO:0008083](https://www.ebi.ac.uk/QuickGO/term/GO:0008083)) by binding to the leukemia inhibitory factor receptor ([GO:0005146](https://www.ebi.ac.uk/QuickGO/term/GO:0005146)). This interaction is a key component of the [Interleukin-6 family signaling](/details-gene/3976) pathway ([R-HSA-6783589](https://reactome.org/content/detail/R-HSA-6783589)) and contributes to the broader network of [Cytokine signaling in immune system](/details-gene/3976) ([R-HSA-1280215](https://reactome.org/content/detail/R-HSA-1280215)). The primary downstream signaling cascade initiated by [LIF](/details-gene/3976) is the [cell surface receptor signaling pathway via stat](/details-gene/3976) ([GO:0097696](https://www.ebi.ac.uk/QuickGO/term/GO:0097696)), which ultimately leads to the regulation of [gene expression](/details-gene/3976) ([GO:0010467](https://www.ebi.ac.uk/QuickGO/term/GO:0010467)). The pleiotropic nature of [LIF](/details-gene/3976) is evident from its involvement in a wide array of biological processes. These include developmental events like [embryo implantation](/details-gene/3976) ([GO:0007566](https://www.ebi.ac.uk/QuickGO/term/GO:0007566)) and [lung alveolus development](/details-gene/3976) ([GO:0048286](https://www.ebi.ac.uk/QuickGO/term/GO:0048286)), as well as cellular differentiation processes such as [positive regulation of macrophage differentiation](/details-gene/3976) ([GO:0045651](https://www.ebi.ac.uk/QuickGO/term/GO:0045651)) and [positive regulation of astrocyte differentiation](/details-gene/3976) ([GO:0048711](https://www.ebi.ac.uk/QuickGO/term/GO:0048711)). Its role in regulating cell growth is dual-faceted, with annotations for both [positive regulation of cell population proliferation](/details-gene/3976) ([GO:0008284](https://www.ebi.ac.uk/QuickGO/term/GO:0008284)) and [negative regulation of cell population proliferation](/details-gene/3976) ([GO:0008285](https://www.ebi.ac.uk/QuickGO/term/GO:0008285)), reflecting its context-specific effects. This functional profile aligns with its observed expression in fibroblasts and epithelial cells, which are key players in organogenesis and tissue repair. ## Research Directions The diverse functions and specific expression pattern of [LIF](/details-gene/3976) suggest several avenues for future research. Its prominent role in stromal and epithelial cells, coupled with its involvement in tissue remodeling and immune signaling, points to its potential importance in both physiological and pathological processes. **Proposed Hypotheses:** 1. Given its high expression in [fibroblast of lung](/details-cell/CL0002553) and its documented role in processes such as [blood vessel remodeling](/details-gene/3976) ([GO:0001974](https://www.ebi.ac.uk/QuickGO/term/GO:0001974)) and [response to hypoxia](/details-gene/3976) ([GO:0001666](https://www.ebi.ac.uk/QuickGO/term/GO:0001666)), fibroblast-derived [LIF](/details-gene/3976) likely acts as a critical mediator of epithelial and endothelial repair in the lung following injury, coordinating cell proliferation and differentiation to restore tissue integrity. 2. The significant expression of [LIF](/details-gene/3976) in [group 3 innate lymphoid cell](/details-cell/CL0001071), a key cell type in mucosal tissues, suggests that ILC3-derived [LIF](/details-gene/3976) is a key cytokine for orchestrating mucosal barrier defense and inflammation, possibly by directly influencing the behavior of nearby epithelial stem cells and Paneth cells. **Experimental Approach:** To test the first hypothesis regarding the role of fibroblast-derived [LIF](/details-gene/3976) in lung repair, a series of *in vitro* and *in vivo* experiments could be designed. A co-culture system using primary human lung fibroblasts and bronchial epithelial cells could be established. Fibroblasts, either wild-type or with a CRISPR-Cas9-mediated knockout of [LIF](/details-gene/3976), would be subjected to hypoxic or inflammatory stimuli. The conditioned media would then be applied to a wounded epithelial monolayer. The effect on wound closure, cell proliferation (e.g., Ki67 staining), and differentiation could be quantified. The requirement for [LIF](/details-gene/3976) could be confirmed by adding a neutralizing antibody or recombinant [LIF](/details-gene/3976) to the system and assessing the rescue of the repair phenotype. **Therapeutic Potential:** As a secreted cytokine, [LIF](/details-gene/3976) is an accessible therapeutic target. Its potential is complex due to its pleiotropic and often contradictory roles (e.g., promoting both cell proliferation and its inhibition). In oncology, where [LIF](/details-gene/3976) can promote tumor cell survival and stemness, **inhibition** via neutralizing antibodies or receptor antagonists represents a viable strategy. Conversely, in regenerative medicine, the ability of [LIF](/details-gene/3976) to maintain stem cell populations ([GO:0035019](https://www.ebi.ac.uk/QuickGO/term/GO:0035019)) and promote tissue repair suggests that targeted **activation** or delivery of recombinant [LIF](/details-gene/3976) could be beneficial for treating degenerative diseases or acute tissue injuries. Therefore, the therapeutic strategy for modulating [LIF](/details-gene/3976) activity must be carefully tailored to the specific disease context.

Genular Protein ID: 2734624317

Symbol: LIF_HUMAN

Name: Leukemia inhibitory factor

UniProtKB Accession Codes:

P15018 B2RCW7 B5MC23 Q52LZ2

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 Bgee 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 2 CORUM 1 CTD 1 DIP 1 DMDM 1 DNASU 1 DisGeNET 1 EMBL 12 EMDB 1 Ensembl 2 EvolutionaryTrace 1 GO 47 Gene3D 1 GeneCards 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 GlyCosmos 1 GlyGen 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 4 KEGG 1 MANE-Select 1 MIM 1 MINT 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 OrthoDB 1 PANTHER 2 PDB 5 PDBsum 5 PIR 1 PRINTS 1 PRO 1 PROSITE 1 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 1 PharmGKB 1 Pharos 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 1 RNAct 1 Reactome 3 RefSeq 2 SIGNOR 1 SMART 1 SMR 1 STRING 1 SUPFAM 1 SignaLink 1 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 neXtProt 1

Citations:

PubMed ID: 3143918

Title: Leukaemia inhibitory factor is identical to the myeloid growth factor human interleukin for DA cells.

PubMed ID: 3143918

DOI: 10.1038/336690a0

PubMed ID: 2475312

Title: Genomic cloning and heterologous expression of human differentiation-stimulating factor.

PubMed ID: 2475312

DOI: 10.1089/dna.1.1989.8.351

PubMed ID: 15146197

Title: Transcriptome characterization elucidates signaling networks that control human ES cell growth and differentiation.

PubMed ID: 15146197

DOI: 10.1038/nbt971

PubMed ID: 1692837

Title: Structural organization of the genes for murine and human leukemia inhibitory factor. Evolutionary conservation of coding and non-coding regions.

PubMed ID: 1692837

DOI: 10.1016/s0021-9258(19)38963-x

PubMed ID: 14702039

Title: Complete sequencing and characterization of 21,243 full-length human cDNAs.

PubMed ID: 14702039

DOI: 10.1038/ng1285

PubMed ID: 10591208

Title: The DNA sequence of human chromosome 22.

PubMed ID: 10591208

DOI: 10.1038/990031

PubMed ID: 15489334

Title: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).

PubMed ID: 15489334

DOI: 10.1101/gr.2596504

PubMed ID: 3128791

Title: Molecular cloning and expression of the human homologue of the murine gene encoding myeloid leukemia-inhibitory factor.

PubMed ID: 3128791

DOI: 10.1073/pnas.85.8.2623

PubMed ID: 2730639

Title: Purification of a lipoprotein lipase-inhibiting protein produced by a melanoma cell line associated with cancer cachexia.

PubMed ID: 2730639

DOI: 10.1016/s0006-291x(89)80114-7

PubMed ID: 8489250

Title: Glycosylation pattern and disulfide assignments of recombinant human differentiation-stimulating factor.

PubMed ID: 8489250

DOI: 10.1006/abbi.1993.1243

PubMed ID: 14527405

Title: Convergent mechanisms for recognition of divergent cytokines by the shared signaling receptor gp130.

PubMed ID: 14527405

DOI: 10.1016/s1097-2765(03)00365-4

PubMed ID: 17652170

Title: An unusual cytokine:Ig-domain interaction revealed in the crystal structure of leukemia inhibitory factor (LIF) in complex with the LIF receptor.

PubMed ID: 17652170

DOI: 10.1073/pnas.0705577104

Sequence Information:

  • Length: 202
  • Mass: 22008
  • Checksum: 634CD10BFF67A217
  • Sequence:
    • MKVLAAGVVP LLLVLHWKHG AGSPLPITPV NATCAIRHPC HNNLMNQIRS QLAQLNGSAN 
ALFILYYTAQ GEPFPNNLDK LCGPNVTDFP PFHANGTEKA KLVELYRIVV YLGTSLGNIT 
RDQKILNPSA LSLHSKLNAT ADILRGLLSN VLCRLCSKYH VGHVDVTYGP DTSGKDVFQK 
KKLGCQLLGK YKQIIAVLAQ AF