GO:0071651 positive regulation of chemokine (C-C motif) ligand 5 production: Signaling Pathway, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0071651 describes any process that activates or increases the frequency, rate, or extent of production of chemokine (C-C motif) ligand 5 (CCL5), also known as RANTES.
• CCL5 is a key chemoattractant for T cells, macrophages, and other leukocytes, and its production is tightly regulated at transcriptional and post-transcriptional levels [1, 6].
• Positive regulation of CCL5 production is implicated in inflammatory diseases, cancer progression, and antiviral responses [2, 3, 6].
• Key signaling pathways include acid sphingomyelinase/ceramide, AP-1, and microRNA-mediated modulation [1, 3, 5].
• Experimental models to study this process include knockout, knock-in, and overexpression cell lines, as well as CRISPR library screening [1, 3, 6].
• Understanding GO:0071651 can guide therapeutic strategies targeting CCL5 in cancer, autoimmunity, and infectious diseases [3, 6].
Description
GO:0071651, positive regulation of chemokine (C-C motif) ligand 5 production, is a biological process that encompasses any mechanism that increases the synthesis or secretion of CCL5 (also known as RANTES). CCL5 is a chemokine that plays a central role in recruiting immune cells to sites of inflammation and infection [1, 6]. The regulation of CCL5 production is critical for mounting effective immune responses, but its dysregulation contributes to chronic inflammatory diseases and cancer progression [2, 3, 6]. Researchers study this process to identify molecular targets that can modulate CCL5 levels for therapeutic benefit [3, 6]. This article synthesizes current knowledge on the mechanisms, genes, and experimental approaches related to GO:0071651, based on authoritative QuickGO data and published literature.
positive regulation of chemokine (C-C motif) ligand 5 production At A Glance
| GO ID | GO:0071651 |
|---|---|
| GO term | positive regulation of chemokine (C-C motif) ligand 5 production |
| Ontology | biological_process |
| Synonym | positive regulation of CCL5 production; positive regulation of RANTES production; positive regulation of Regulated upon Activation, Normal T-cell Expressed, and Secreted production |
| Major function | Increases the production of CCL5, a chemokine involved in immune cell recruitment and inflammation |
| Related pathways | Acid sphingomyelinase/ceramide signaling, AP-1 transcription, microRNA regulation |
| Disease relevance | Cancer, inflammatory diseases, viral infections |
| Research methods | CRISPR knockout, overexpression, RNA-seq, proteomics |
What Is GO:0071651?
According to the Gene Ontology, GO:0071651 is defined as any process that activates or increases the frequency, rate, or extent of production of chemokine (C-C motif) ligand 5. This includes transcriptional activation, enhanced mRNA stability, increased translation, and facilitated secretion of the CCL5 protein [1, 3]. The term is a child of positive regulation of chemokine production and is specific to CCL5, distinguishing it from regulation of other chemokines.
Why Is positive regulation of chemokine (C-C motif) ligand 5 production Important in Cell Biology?
Understanding positive regulation of CCL5 production is crucial because CCL5 is a pivotal mediator of immune cell trafficking and inflammation [1, 6]. Dysregulated CCL5 production is associated with a wide range of pathologies, including cancer, autoimmune diseases, and chronic inflammatory conditions [2, 3, 6]. By elucidating the mechanisms that upregulate CCL5, researchers can identify novel therapeutic targets to modulate immune responses [3, 6].
• CCL5 is a major chemoattractant for T cells, monocytes, and eosinophils, linking innate and adaptive immunity.
• Positive regulation of CCL5 production is essential for antiviral and antitumor immune responses [3, 5].
• Overexpression of CCL5 is observed in inflammatory diseases such as oral lichen planus and allergic rhinitis [2, 7].
• CCL5 promotes tumor progression and immunosuppression in clear cell renal cell carcinoma.
• Modulating CCL5 production can enhance immunotherapy efficacy, as shown with eravacycline in melanoma.
• MicroRNAs such as miR-19b-3p can modulate CCL5 production during viral encephalitis.
• Acid sphingomyelinase and acid ceramidase regulate CCL5/RANTES production, linking lipid metabolism to chemokine regulation.
• Retinoic acid signaling can modulate asthma manifestations via chemokine regulation.
• CCL5 production is a potential biomarker for inflammatory conditions [2, 7].
• Targeting positive regulation of CCL5 production may offer therapeutic strategies for cancer and inflammatory diseases [3, 6].
What Happens During positive regulation of chemokine (C-C motif) ligand 5 production?
Transcriptional Activation of CCL5
In simple terms: The cell receives signals that turn on the CCL5 gene, leading to more mRNA being made.
Transcriptional activation of the CCL5 gene is a key step in positive regulation. Various stimuli, such as inflammatory cytokines and pathogen-associated molecular patterns, activate transcription factors like AP-1 and NF-kB, which bind to the CCL5 promoter and enhance transcription [1, 3]. For example, eravacycline treatment in melanoma cells increases AP-1 activity, leading to upregulated CCL5 production. This transcriptional upregulation is essential for rapid chemokine release during immune responses.
Post-transcriptional Regulation of CCL5 mRNA
In simple terms: After the mRNA is made, its stability and translation can be increased or decreased by other molecules.
Post-transcriptional mechanisms, including mRNA stability and microRNA-mediated regulation, fine-tune CCL5 production. MicroRNA-19b-3p modulates Japanese encephalitis virus-mediated inflammation by targeting RNF11, which affects CCL5 production. Additionally, acid sphingomyelinase and acid ceramidase regulate CCL5/RANTES at the post-transcriptional level, as shown in studies using pharmacological inhibitors. These mechanisms ensure precise control of CCL5 levels in response to environmental cues.
Secretion and Extracellular Release of CCL5
In simple terms: The CCL5 protein is packaged and released from the cell to attract immune cells.
Once produced, CCL5 is secreted into the extracellular space, where it acts as a chemoattractant. Secretion can be enhanced by positive regulatory signals. For instance, in clear cell renal cell carcinoma, tumor-associated macrophages release CCL5, which facilitates tumor progression and an immunosuppressive microenvironment. The secretion process involves vesicular transport and can be influenced by lipid metabolism pathways.
Feedback and Amplification Loops
In simple terms: Once CCL5 is released, it can trigger more CCL5 production, creating a positive feedback loop.
Positive regulation of CCL5 production can involve feedback amplification. For example, CCL5 released from cells can recruit additional immune cells that secrete more CCL5, amplifying the inflammatory response [1, 6]. In melanoma, eravacycline-induced CCL5 production promotes M1 macrophage polarization, which further enhances antitumor immunity. Such loops are critical for sustaining immune responses but can also contribute to chronic inflammation if unchecked.
Key Genes Involved in GO:0071651 positive regulation of chemokine (C-C motif) ligand 5 production
The following genes and proteins are key players in the positive regulation of CCL5 production, based on published literature.
| Gene | Major Role | Research Relevance |
|---|---|---|
| CCL5 | Encodes the chemokine CCL5/RANTES | Central to the process; target for modulation |
| SMPD1 | Acid sphingomyelinase, regulates CCL5 production | Lipid metabolism link to chemokine regulation |
| ASAH1 | Acid ceramidase, regulates CCL5 production | Lipid metabolism link to chemokine regulation |
| AP1 | Transcription factor complex activating CCL5 | Mediates eravacycline-induced CCL5 in melanoma |
| RNF11 | E3 ubiquitin ligase, modulated by miR-19b-3p | Affects CCL5 production in viral encephalitis |
| MIR19B3 | MicroRNA-19b-3p, targets RNF11 | Modulates inflammation and CCL5 |
| TNF | Pro-inflammatory cytokine, induces CCL5 | Common stimulus for CCL5 production |
| IL1B | Interleukin-1 beta, induces CCL5 | Inflammatory mediator |
| IFNG | Interferon gamma, induces CCL5 | Antiviral and immune responses |
| NFKB1 | Transcription factor, activates CCL5 | Inflammatory signaling |
| STAT1 | Transcription factor, induced by IFN | Antiviral responses |
| CCR5 | Receptor for CCL5 | Mediates CCL5 effects |
| CD8A | T cell marker, recruited by CCL5 | Immune cell recruitment |
| CD68 | Macrophage marker, recruited by CCL5 | Immune cell recruitment |
| ITGAM | Macrophage marker, involved in CCL5 response | Immune cell recruitment |
| LYZ | Macrophage marker, involved in CCL5 response | Immune cell recruitment |
| PTPRC | CD45, leukocyte marker | Immune cell recruitment |
How Is positive regulation of chemokine (C-C motif) ligand 5 production Regulated?
Positive regulation of CCL5 production is controlled by multiple signaling pathways. Acid sphingomyelinase and acid ceramidase regulate CCL5/RANTES production, linking lipid metabolism to chemokine regulation. The AP-1 transcription factor complex mediates eravacycline-induced CCL5 production in melanoma, enhancing anti-PD1 immunotherapy efficacy. MicroRNA-19b-3p modulates CCL5 production by targeting RNF11 during Japanese encephalitis virus infection. Additionally, retinoic acid signaling can modulate asthma manifestations, potentially through chemokine regulation. These regulatory mechanisms provide potential targets for therapeutic intervention.
positive regulation of chemokine (C-C motif) ligand 5 production and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| CCL5 | Clear cell renal cell carcinoma | Knockout or overexpression in renal cancer cell lines |
| CCL5 | Melanoma immunotherapy | Overexpression in melanoma cells with anti-PD1 treatment |
| CCL5 | Oral lichen planus | Knockdown in oral keratinocytes |
| CCL5 | Allergic rhinitis | Overexpression in nasal epithelial cells |
| CCL5 | Japanese encephalitis | Knockout in neuronal cells |
CCL5 in Cancer Progression and Immunotherapy
CCL5 produced by tumor-associated macrophages facilitates the progression and immunosuppressive tumor microenvironment of clear cell renal cell carcinoma. In melanoma, eravacycline improves the efficacy of anti-PD1 immunotherapy via AP1/CCL5-mediated M1 macrophage polarization. These findings highlight the dual role of CCL5 in cancer: it can promote tumor progression but also enhance antitumor immunity when properly modulated [3, 6].
CCL5 in Inflammatory and Autoimmune Diseases
CCL5 is elevated in inflammatory conditions such as oral lichen planus and oral lichenoid lesions, as shown in a systematic review. Nonselective chemokine levels, including CCL5, are increased in nasal secretions of patients with perennial nonallergic and allergic rhinitis. These observations suggest that positive regulation of CCL5 production contributes to the pathogenesis of these inflammatory diseases [2, 7].
CCL5 in Viral Infections and Neuroinflammation
MicroRNA-19b-3p modulates Japanese encephalitis virus-mediated inflammation via targeting RNF11, affecting CCL5 production. This indicates that positive regulation of CCL5 is part of the antiviral response but may also contribute to neuroinflammation. Understanding these mechanisms could inform therapies for viral encephalitis and other neuroinflammatory conditions.
From positive regulation of chemokine (C-C motif) ligand 5 production-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does gene X regulate CCL5 production? | CRISPR knockout of gene X in immune or cancer cells [1, 3] |
| Does a point mutation in gene Y affect CCL5 levels? | Point mutation knock-in using CRISPR |
| Can overexpression of gene Z increase CCL5 production? | Overexpression cell line via lentiviral transduction |
| What is the role of a tagged protein in CCL5 regulation? | Tagged knock-in for imaging or immunoprecipitation |
| Which genes are essential for CCL5 production? | CRISPR library screening |
| How does CCL5 production change in disease? | Patient-derived organoids or xenografts |
How to Study the positive regulation of chemokine (C-C motif) ligand 5 production Process
| Method | What It Measures | Typical Application |
|---|---|---|
| RNA-seq | mRNA levels of CCL5 and related genes | Transcriptional regulation studies [1, 3] |
| ELISA | Secreted CCL5 protein | Quantification of CCL5 production |
| Western blot | Intracellular CCL5 protein | Protein expression analysis |
| CRISPR screen | Genes affecting CCL5 production | Discovery of regulators |
| Flow cytometry | CCL5+ cells and immune cell populations | Immune cell recruitment |
| Immunofluorescence | Localization of CCL5 | Tissue imaging |
| qPCR | CCL5 mRNA levels | Validation of expression changes |
| Luminex | Multiple chemokines including CCL5 | Multiplex cytokine profiling |
Transcriptomic Analysis
RNA-seq can quantify CCL5 mRNA levels and identify transcriptional changes under conditions that positively regulate CCL5 production [1, 3]. This method is useful for discovering upstream regulators and pathways.
Proteomic and Secretome Analysis
Proteomics and secretome analysis can measure CCL5 protein levels in cell supernatants, providing insights into secretion dynamics [1, 6]. ELISA is commonly used to quantify secreted CCL5.
CRISPR Screening
Genome-wide CRISPR screens can identify genes that positively regulate CCL5 production when knocked out or overexpressed. This approach is powerful for discovering novel regulators.
Imaging and Flow Cytometry
Flow cytometry can detect intracellular CCL5 and surface markers, while imaging can visualize CCL5 trafficking in cells. These methods help localize CCL5 production and secretion.
How CRISPR Can Be Used to Study GO:0071651 positive regulation of chemokine (C-C motif) ligand 5 production
Knockout
CRISPR knockout of candidate genes can determine whether they are necessary for positive regulation of CCL5 production. For example, knocking out SMPD1 or ASAH1 reduces CCL5 production, confirming their roles. Knockout models are essential for loss-of-function studies [1, 3].
Point Mutation
Point mutations can be introduced to study specific amino acid residues or regulatory elements. For instance, mutating AP-1 binding sites in the CCL5 promoter can reveal their importance in transcriptional activation. This approach provides mechanistic insights.
Knock-in
Knock-in of tagged CCL5 or regulatory proteins allows for tracking and purification. Tagged knock-in models can be used to study CCL5 secretion dynamics. This is valuable for understanding real-time regulation.
Overexpression
Overexpression of candidate genes can test sufficiency for CCL5 induction. For example, overexpressing AP-1 components increases CCL5 production. Overexpression models are useful for gain-of-function studies [3, 6].
How EDITGENE Supports positive regulation of chemokine (C-C motif) ligand 5 production Research
Researchers studying positive regulation of chemokine (C-C motif) ligand 5 production-related genes often need to determine whether a candidate gene is causally involved in upregulating CCL5. EDITGENE provides comprehensive CRISPR-based services to address these questions with precision and reliability.
Contact EDITGENE today to design your custom CRISPR model for positive regulation of chemokine (C-C motif) ligand 5 production research.
Frequently Asked Questions About positive regulation of chemokine (C-C motif) ligand 5 production
What is GO:0071651?
GO:0071651 is the Gene Ontology term for positive regulation of chemokine (C-C motif) ligand 5 production, describing processes that increase CCL5 levels.
What genes are involved in positive regulation of CCL5 production?
Key genes include CCL5 itself, SMPD1, ASAH1, AP1, RNF11, and MIR19B3, among others [1, 3, 5].
How is CCL5 production regulated?
CCL5 production is regulated at transcriptional, post-transcriptional, and secretory levels by pathways such as acid sphingomyelinase/ceramide and AP-1 [1, 3].
What diseases are associated with CCL5 overproduction?
CCL5 overproduction is linked to cancer, oral lichen planus, allergic rhinitis, and neuroinflammation [2, 3, 6, 7].
What experimental models are used to study CCL5 regulation?
CRISPR knockout, knock-in, overexpression cell lines, and CRISPR screens are commonly used [1, 3, 6].
How can I measure CCL5 production?
ELISA, Western blot, RNA-seq, and flow cytometry are standard methods [1, 6].
What is the role of CCL5 in cancer?
CCL5 can promote tumor progression and immunosuppression, but also enhance antitumor immunity in some contexts [3, 6].
Can CCL5 production be targeted therapeutically?
Yes, modulating CCL5 production is a potential strategy for cancer immunotherapy and inflammatory diseases [3, 6].
What is the difference between CCL5 and RANTES?
CCL5 and RANTES refer to the same chemokine; RANTES is an older name.
How does EDITGENE support CCL5 research?
EDITGENE provides CRISPR knockout, knock-in, overexpression models, library screening, and bioinformatics for CCL5-related studies [1, 3, 6].
Conclusion
Positive regulation of chemokine (C-C motif) ligand 5 production (GO:0071651) is a critical biological process with broad implications for immunity, inflammation, and cancer. Understanding its mechanisms and regulators can lead to novel therapeutic strategies. EDITGENE offers a suite of CRISPR-based tools to dissect this process and accelerate discovery.
References
- 1. Jenkins RW et al.. 2011. Regulation of CC ligand 5/RANTES by acid sphingomyelinase and acid ceramidase.. J Biol Chem 286(15):13292-303 PMID: 21335555
- 2. Rampersaud E et al.. 2026. Expression of the Chemokine (C-C Motif) Ligand 5 (CCL5) in Oral Lichen Planus and Oral Lichenoid Lesions: A Systematic Review.. J Oral Pathol Med PMID: 42394224
- 3. Liu N et al.. 2025. Eravacycline improves the efficacy of anti-PD1 immunotherapy via AP1/CCL5 mediated M1 macrophage polarization in melanoma.. Biomaterials 314:122815 PMID: 39288620
- 5. Ashraf U et al.. 2016. MicroRNA-19b-3p Modulates Japanese Encephalitis Virus-Mediated Inflammation via Targeting RNF11.. J Virol 90(9):4780-4795 PMID: 26937036
- 6. Xu W et al.. 2022. Tumor-associated macrophage-derived chemokine CCL5 facilitates the progression and immunosuppressive tumor microenvironment of clear cell renal cell carcinoma.. Int J Biol Sci 18(13):4884-4900 PMID: 35982911
- 7. Perić A et al.. 2016. Nonselective chemokine levels in nasal secretions of patients with perennial nonallergic and allergic rhinitis.. Int Forum Allergy Rhinol 6(4):392-7 PMID: 26679085
- 8. Maret M et al.. 2007. Liposomal retinoic acids modulate asthma manifestations in mice.. J Nutr 137(12):2730-6 PMID: 18029491
