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IL1A

Official Full Name
interleukin 1 alpha
Organism
Homo sapiens
GeneID
3552
Background
The protein encoded by this gene is a member of the interleukin 1 cytokine family. This cytokine is a pleiotropic cytokine involved in various immune responses, inflammatory processes, and hematopoiesis. This cytokine is produced by monocytes and macrophages as a proprotein, which is proteolytically processed and released in response to cell injury, and thus induces apoptosis. This gene and eight other interleukin 1 family genes form a cytokine gene cluster on chromosome 2. It has been suggested that the polymorphism of these genes is associated with rheumatoid arthritis and Alzheimer's disease. [provided by RefSeq, Jul 2008]
Synonyms
IL1; IL-1A; IL1F1; IL1-ALPHA; IL-1 alpha;
Bio Chemical Class
Cytokine: interleukin
Protein Sequence
MAKVPDMFEDLKNCYSENEEDSSSIDHLSLNQKSFYHVSYGPLHEGCMDQSVSLSISETSKTSKLTFKESMVVVATNGKVLKKRRLSLSQSITDDDLEAIANDSEEEIIKPRSAPFSFLSNVKYNFMRIIKYEFILNDALNQSIIRANDQYLTAAALHNLDEAVKFDMGAYKSSKDDAKITVILRISKTQLYVTAQDEDQPVLLKEMPEIPKTITGSETNLLFFWETHGTKNYFTSVAHPNLFIATKQDYWVCLAGGPPSITDFQILENQA
Open
Disease
Acne vulgaris, Arterial occlusive disease, Atopic eczema, Chronic arterial occlusive disease, Colorectal cancer, Hidradenitis suppurativa, Influenza, Lung cancer, Osteoarthritis, Psoriasis, Pyoderma gangrenosum, Rheumatoid arthritis, Type 2 diabetes mellitus
Approved Drug
0
Clinical Trial Drug
5 +
Discontinued Drug
2 +

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Detailed Information

Interleukin-1 alpha (IL-1α) is a critical cytokine belonging to the interleukin-1 family, which plays a central role in regulating immune responses, inflammation, and hematopoiesis. As an inactive precursor, it is mostly generated by macrophages and monocytes. It undergoes proteolytic processing upon cell damage to become its active form, which can then start a series of biological reactions including apoptosis. Housed in a cluster of interleukin 1 family genes on chromosome 2, the gene producing IL-1α has been linked to several disorders by polymorphisms in these genes, including rheumatoid arthritis and Alzheimer's disease.

IL-1α not only acts as an inflammatory mediator but also as an alarmin, warning the immune system of cell injury. Important for inflammation and immunological responses, this protein participates in several signaling pathways, including those linked to the activation of NF-\u03baB and different MAPK pathways. Its association with IL-1RI and IL-1RII stimulates downstream pathways generating cytokines and cell death. Given its central importance in disease processes, IL-1α has become a target for therapeutic approaches, particularly in inflammatory and autoimmune diseases.

Structure and Functional Domains of IL-1α

Comprising 271 amino acids, the IL-1α protein is split into three primary structural domains: the N-terminal domain, the central domain, and the C-terminal domain. Every one of these areas has particular functions for the protein:

1. N-terminal domain (1-79 amino acids): This region contains a nuclear localization signal (NLS), which facilitates the entry of IL-1α into the cell nucleus, enabling it to influence transcription regulation.

2. Central domain (80-263 amino acids): This part houses multiple functional motifs, including sites for myristoylation and phosphorylation. These modifications are essential for the protein's signaling and regulatory functions.

3. C-terminal domain (264-271 amino acids): The C-terminal region contains a binding site for actin, suggesting a role for IL-1α in cytoplasmic processes.

Crucial for its activation and function, IL-1α experiences many proteolytic cleavages. These consist of chymase, calpain, elastase, thrombin, and caspase enzyme cleaving. Such changes let IL-1α go from its precursor form to its active state, hence allowing it to perform its biological activities. Especially in reaction to cellular stress and damage, the existence of these cleavage sites helps to illuminate the regulatory mechanisms governing IL-1α activity.

Figure 1 illustrates the synthesis and signal transduction pathway of IL-1alpha and IL-1beta.Figure 1. IL-1alpha and IL-1beta synthesis and signal transduction pathway. (Risbud MV, et al., 2014)

IL-1α in Normal and Tumor Tissues

Various cell types, including monocytes, macrophages, and keratinocytes, express IL-1α. IL-1α is mostly found in the nucleus of normal tissues where it helps control genes. It moves to the extracellular space during inflammatory circumstances or cellular stress, where it triggers inflammatory pathways.

In terms of cancer, IL-1α is quite important for tumor growth. Involved in fostering tumor development, invasion, and metastasis, IL-1α is secreted by tumor-associated macrophages (TAMs), neutrophils, and the tumor cells themselves. It has been implicated in several cancer types, including breast cancer, oral squamous cell carcinoma, pancreatic cancer, and renal cell carcinoma. For instance, IL-1α in breast cancer contributes to tumor cell proliferation and invasion by activating the NF-κB/IL-6 feedback loop. In pancreatic cancer, it enhances anti-tumor immune responses and promotes tumor cell migration.

Mechanisms of IL-1α Signaling and Regulation

IL-1α exerts its effects by binding to its receptors, IL-1RI and IL-1RII. IL-1RI is the primary receptor, triggering a strong inflammatory response when it forms a complex with the accessory protein IL-1RAcP. This binding activates several downstream signaling pathways, including NF-κB, MAPKs (ERK, JNK, p38), and JAK/STAT pathways, which mediate the expression of pro-inflammatory cytokines.

The binding of IL-1α to IL-1RI leads to receptor dimerization, which activates various signaling molecules such as MyD88, IRAK1/4, and TRAF6, all of which contribute to NF-κB activation. This, in turn, induces the transcription of inflammatory cytokines such as IL-6 and TNF-α. In addition to its role in inflammation, IL-1α also influences cell proliferation, migration, and apoptosis. It acts as a signal for genotoxic stress and plays a role in DNA damage responses, further highlighting its importance in cellular homeostasis.

Moreover, IL-1α signaling is tightly regulated by feedback mechanisms. The IL-1 receptor antagonist (IL-1Ra) competes with IL-1α for binding to IL-1RI, effectively blocking its action and thus preventing excessive inflammation. These regulatory processes are critical for maintaining balance in the immune response.

IL-1α in Disease and Therapeutic Development

Because IL-1α is involved in inflammatory diseases, autoimmune diseases, and cancer, it has been chosen as a target for treatment. IL-1α amounts that are too high are linked to many illnesses, including rheumatoid arthritis, heart disease, brain disorders, and cancer. By encouraging inflammation and immune system activity, IL-1α plays a part in how these conditions get worse.

IL-1α helps the inflammatory microenvironment in cancer, which makes it easier for the tumor to grow and spread. A lot of different types of cancer, including breast, pancreatic, and kidney cancer, have been linked to it. By going after IL-1α or its receptor, these inflammation pathways can be changed, which might slow the growth of cancer.

Creating monoclonal antibodies, small chemical inhibitors, and synthetic proteins are some ways to target IL-1α as a therapeutic target. Anakinra is a recombinant IL-1 receptor blocker, and Canakinumab is a monoclonal antibody against IL-1α. These drugs have the potential to help treat rheumatoid arthritis, systemic juvenile idiopathic arthritis, and some types of cancer. Bekimumab, an anti-IL-1α monoclonal antibody, has been tried in clinical studies as a cancer drug and may help people with advanced colon cancer have a better chance of living longer.

IL-1α-targeted treatments do, however, offer new ways to treat inflammatory and autoimmune illnesses, but they may also have side effects. Some of these are immunosuppression, which can make you more likely to get infections, and other problems like skin itching, tiredness, and stomach pain. More research is being done in clinical studies to find the best ways to lessen these side effects while still getting the most out of the therapy.

References:

  1. Harati-Sadegh M, Sargazi S, Khorasani M, et al. IL1A and IL1B gene polymorphisms and keratoconus susceptibility: evidence from an updated meta-analysis. Ophthalmic Genet. 2021;42(5):503-513.
  2. Risbud MV, Shapiro IM. Role of cytokines in intervertebral disc degeneration: pain and disc content. Nat Rev Rheumatol. 2014;10(1):44-56.
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