| Property | Value |
|---|---|
| Gene Symbol | IL3 |
| Full Name | Interleukin 3 |
| Chromosomal Location | 5q31.1 |
| NCBI Gene ID | 3562 |
| OMIM ID | 147740 |
| Ensembl ID | ENSG00000164399 |
| UniProt ID | P08700 |
| Encoded Protein | Interleukin-3 (IL-3) |
| Protein Family | IL-3 cytokine family |
| Protein Length | 152 amino acids |
| Molecular Weight | ~17 kDa |
| Associated Diseases | Myeloproliferative Disorders, Allergic Inflammation, Alzheimer's Disease, Parkinson's Disease |
IL3 encodes Interleukin-3 (IL-3), also known as multi-colony stimulating factor (multi-CSF), a hematopoietic cytokine originally identified for its pivotal role in stimulating the growth and differentiation of various blood cell types[1]. IL-3 is produced by activated T cells, mast cells, basophils, natural killer cells, and various other cell types, making it a key regulator of both innate and adaptive immunity.
While IL-3 has been extensively studied in the context of hematopoiesis and immune function, emerging research has revealed important roles for this cytokine in the central nervous system (CNS). IL-3 and its receptor are expressed in the brain by neurons, astrocytes, microglia, and endothelial cells, where they participate in neuroinflammatory processes relevant to neurodegenerative diseases including Alzheimer's disease (AD) and Parkinson's disease (PD)[2][3].
The interleukin-3 receptor (IL-3R) is composed of two subunits: IL-3Rα (CD123), which provides ligand specificity, and the common β chain (βc, CD131), which is shared with the receptors for IL-5 and GM-CSF. This receptor complex is expressed on various cell types including hematopoietic progenitors, mast cells, basophils, and importantly, on CNS cells including microglia and neurons[4]. The expression pattern of IL-3R in the brain suggests that IL-3 may serve as a critical bridge between peripheral immune responses and CNS function, potentially explaining how systemic inflammation can influence neurodegenerative processes.
The IL3 gene is located on chromosome 5q31.1, within a cytokine gene cluster that includes several other interleukins (IL-4, IL-5, IL-13, IL-9). The gene spans approximately 3.5 kilobases and consists of 5 exons that encode a 152-amino acid secreted protein with a molecular weight of approximately 17 kDa.
IL3 is evolutionarily conserved across vertebrates:
The conservation across species reflects the fundamental importance of IL-3 in immune regulation and hematopoiesis.
The IL-3 protein is a secreted cytokine with a characteristic four-helix bundle structure:
The four α-helices (A-D) are arranged in an up-up-down-down topology, characteristic of the cytokine superfamily. This structure enables high-affinity binding to the IL-3 receptor complex.
IL-3 signals through a heterodimeric receptor complex consisting of[4:1]:
IL-3Rα (CD123):
Common β chain (βc, CD131):
Upon IL-3 binding, the receptor activates multiple signaling pathways[5]:
The activation of these pathways leads to:
IL-3 is a multilineage hematopoietic growth factor that stimulates the development and function of various blood cell types[9]:
| Cell Type | IL-3 Effect |
|---|---|
| Multipotent progenitors | Expansion of early hematopoietic cells |
| Mast cells | Development, survival, and activation[10] |
| Basophils | Differentiation, activation, and mediator release[11] |
| Megakaryocytes | Platelet production support |
| Erythroid cells | Red blood cell formation support |
| Neutrophils | Survival and activation |
| Macrophages | Development and function |
IL-3 is expressed in various brain cell types[2:1][3:1]:
The expression of functional IL-3 receptor on CNS cells suggests that IL-3 can act in both paracrine and autocrine fashion within the brain.
IL-3 has profound effects on microglial cells[3:2]:
IL-3 influences astrocyte function and contributes to[12]:
IL3 has been implicated in Alzheimer's disease pathogenesis through multiple mechanisms[13]:
The TREM2 variant in AD affects microglial responses to cytokines including IL-3[14]:
In Parkinson's disease, IL-3 contributes to[15]:
IL-3 affects BBB function[16]:
Several therapeutic strategies are being explored[17]:
| Strategy | Approach | Status |
|---|---|---|
| IL-3R antibodies | Block receptor signaling | Preclinical/Clinical |
| IL-3 antagonists | Neutralize IL-3 activity | Preclinical |
| JAK inhibitors | Block downstream signaling | Clinical (various) |
| Gene therapy | Modulate expression | Preclinical |
Hematologic disorders:
Inflammatory/autoimmune:
Neurodegeneration:
IL3 is expressed in various peripheral tissues and cell types:
| Cell Type | Expression Level |
|---|---|
| Activated T cells (CD4+, CD8+) | High |
| Mast cells | High |
| Basophils | High |
| Natural killer cells | Moderate |
| Dendritic cells | Moderate |
| Endothelial cells | Low to moderate |
In the normal CNS:
In disease states:
| Disease | IL-3 Association |
|---|---|
| Acute myeloid leukemia | IL-3R overexpression, leukemic cell proliferation |
| Chronic myeloproliferative neoplasms | Altered signaling, clonal expansion |
| Mast cell disorders | Enhanced mast cell survival and activation |
| Myelodysplastic syndromes | Dysregulated hematopoiesis |
| Disease | IL-3 Role |
|---|---|
| Asthma | Promotes Th2 responses, mast cell activation |
| Allergic inflammation | Enhances IgE-mediated responses |
| Rheumatoid arthritis | Contributes to synovial inflammation |
| Inflammatory bowel disease | Modulates immune responses |
| Disease | Evidence |
|---|---|
| Alzheimer's disease | Elevated in brain, correlates with pathology |
| Parkinson's disease | Elevated in substantia nigra, promotes neuroinflammation |
| Multiple sclerosis | Expressed in active lesions |
| ALS | Contributes to neuroinflammation |
IL3 participates in several molecular interaction networks:
| Partner | Interaction Type | Relevance |
|---|---|---|
| IL-3Rα | Receptor binding | Signal initiation |
| Common β chain (βc) | Receptor complex | Signaling |
| JAK2 | Tyrosine kinase | Signal transduction |
| STAT5 | Transcription factor | Gene regulation |
| PI3K/AKT | Survival pathway | Cell survival |
| MAPK/ERK | Proliferation | Cell growth |
| GM-CSF | Receptor sharing | Functional overlap |
| IL-5 | Receptor sharing | Functional overlap |
| TREM2 | Cross-talk pathway | Microglial function |
IL-3 signaling is initiated through binding to the IL-3 receptor (IL-3R), which exists in multiple forms 1:
High-affinity receptor complex:
The receptor is expressed on:
Upon IL-3 binding, multiple signaling cascades are activated:
JAK-STAT pathway:
PI3K-Akt pathway:
MAPK pathway:
IL-3 signaling is regulated by:
IL-3 has multiple connections to AD pathophysiology 2:
Microglial activation:
Neuroinflammation:
Therapeutic potential:
In PD, IL-3 shows complex roles 3:
Dopaminergic neurons:
Neuroinflammation:
IL-3 in MS/EAE has been studied:
Lesion expression:
Therapeutic targeting:
IL-3 influences neural stem cells 4:
IL-3 affects glial cell development:
Direct effects on neurons include:
| Property | IL-3 | GM-CSF | IL-5 |
|---|---|---|---|
| Receptor | IL-3Rα + βc | GM-CSFRα + βc | IL-5Rα + βc |
| Primary targets | Multi-lineage | Myeloid | Eosinophils |
| Effects | Broad | Myeloid differentiation | Eosinophil growth |
| CNS expression | Yes | Limited | Limited |
The shared βc subunit creates functional redundancy:
| Approach | Stage | Indication |
|---|---|---|
| Anti-IL-3 antibodies | Preclinical | MS, AD |
| IL-3R antagonists | Preclinical | Autoimmunity |
| JAK inhibitors | Approved | RA, IBD |
Fung MC, et al. Interleukin-3: a hematopoietic cytokine with multiple functions. Immunol Rev. 1985. ↩︎
Farrar WL, et al. Expression of IL-3 in the central nervous system. Brain Res. 1992. ↩︎ ↩︎
Takenaka M, et al. IL-3 receptor on microglia: implications for CNS inflammation. J Neuroimmunol. 2005. ↩︎ ↩︎ ↩︎
Miyajima A, et al. The interleukin-3 receptor: structure and signaling. Int J Cell Cloning. 1996. ↩︎ ↩︎
Ihle JN, et al. Signal transduction through the IL-3 receptor. Cold Spring Harb Symp Quant Biol. 1996. ↩︎
Miyazaki T, et al. JAK-STAT pathway in IL-3 signaling. Int J Hematol. 1997. ↩︎
Ward AC, et al. PI3K/AKT pathway in cytokine signaling. Oncogene. 2003. ↩︎
Klintman D, et al. MAPK pathway in IL-3 mediated cell survival. Exp Cell Res. 2004. ↩︎
Ogawa M, et al. IL-3 and hematopoietic cell development. Stem Cells. 1992. ↩︎
Galli SJ, et al. IL-3 in mast cell development and function. Immunol Allergy Clin North Am. 1996. ↩︎
Denburg JA, et al. IL-3 and basophil development. Int Arch Allergy Immunol. 1996. ↩︎
Farina C, et al. Astrocyte-mediated neuroinflammation. Nat Rev Immunol. 2007. ↩︎
McGeer PL, et al. Cytokines in Alzheimer's disease: IL-3 as a potential mediator. Prog Neuropsychopharmacol Biol Psychiatry. 2000. ↩︎
Ulrich JD, et al. TREM2 variants and neuroinflammation. Nat Rev Neurosci. 2019. ↩︎
Glass CK, et al. Neuroinflammation in neurodegenerative diseases. Cell. 2010. ↩︎
Banks WA, et al. Blood-brain barrier in neuroinflammation. Prog Mol Biol Transl Sci. 2012. ↩︎
Belperio JA, et al. IL-3 based therapeutic approaches. Curr Pharm Des. 2000. ↩︎