IL-1 Family
Available Resources for the Study of IL-1 Family
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About IL-1 Family
The IL-1 (Interleukin-1) family is a group of cytokines and receptors that play essential roles in regulating immune responses, inflammation, and various physiological processes. The family consists of both agonistic and antagonistic molecules that interact with specific receptors, initiating downstream signaling cascades. Here is an introduction to the IL-1 family, including receptors, ligands, and signaling molecules:
IL-1 Family Receptors
The IL-1 family receptors are transmembrane proteins responsible for recognizing the IL-1 ligands. They include:
- IL-1 receptor type I (IL-1R1): Binds to IL-1α and IL-1β.
- IL-1 receptor type II (IL-1R2): Serves as a decoy receptor that competes with IL-1R1 for ligand binding.
- IL-1 receptor accessory protein (IL-1RAcP): Acts as a co-receptor and is shared across multiple IL-1 family members.
IL-1 Family Ligands
The IL-1 family ligands are cytokines that bind to the IL-1 family receptors, triggering signaling pathways. Some prominent members include:
- IL-1α: Proinflammatory cytokine involved in immune responses and inflammation.
- IL-1β: Potent proinflammatory cytokine that plays a crucial role in infection, tissue damage, and autoimmune diseases.
- IL-18: Involved in immune regulation, promoting the production of interferon-gamma (IFN-γ) and activating natural killer (NK) cells.
- IL-33: Important in promoting Th2 immune responses and activating various immune cells.
IL-1 Family Signaling Molecules
The IL-1 family signaling pathway involves several key molecules, including:
- IL-1 receptor-associated kinases (IRAKs): IRAK2 and IRAK4 are key signaling molecules that interact with IL-1 receptors and initiate downstream signaling events.
- IκB kinases (IKKs): CHUK (IKKα) and IKBKE (IKKε) phosphorylate inhibitor of kappa-B (IκB) proteins, leading to NF-κB activation.
- NF-κB: Nuclear factor kappa-B is a transcription factor that regulates the expression of genes involved in immune responses and inflammation.
- MAPKs: MAPK pathways, including ERKs, JNKs, and p38 MAPKs, are activated downstream of IL-1 receptors and regulate cellular responses to inflammation and stress.
- TRAF6: TNF receptor-associated factor 6 acts as an adaptor protein, facilitating the activation of downstream signaling pathways, including NF-κB and MAPKs.
The activation of IL-1 family receptors leads to the recruitment and activation of intracellular signaling molecules, including IRAKs and TRAFs. This triggers downstream signaling pathways, such as NF-κB and MAPKs, resulting in gene expression alterations and the production of inflammatory cytokines, chemokines, and other immune response mediators.
Table.1 The IL-1 family members. (Kaneko N, et al., 2019)
| IL-1 family members | Receptor | Property |
|---|---|---|
| IL-1α | IL-1RI | Inflammatory |
| IL-1β | IL-1RI | Inflammatory |
| IL-1Ra | IL-1RI | IL-1RI antagonist |
| IL-18 | IL-18Rα | Inflammatory |
| IL-33 | ST2 | Th2 inflammation |
| IL-36Ra | IL-1Rrp2 | IL-1Rrp2 antagonist |
| IL-36α | IL-1Rrp2 | Inflammatory |
| IL-36β | IL-1Rrp2 | Inflammatory |
| IL-36γ | IL-1Rrp2 | Inflammatory |
| IL-37 | IL-18Rα | Anti-inflammatory |
| IL-38 | IL-1Rrp2 | IL-1Rrp2 antagonist |
Detailed Mechanism of IL-1 Family Signaling Pathway
The IL-1 family signaling pathway involves a series of molecular events that lead to the activation of downstream signaling pathways, including the NF-κB and MAPK pathways. Here is a detailed mechanism of IL-1 family signaling:
1. Ligand Binding: The IL-1 family ligands, such as IL-1α, IL-1β, and IL-18, bind to their respective receptors on the cell surface. IL-1α and IL-1β bind to IL-1 receptor type 1 (IL-1R1), while IL-18 binds to IL-18 receptor (IL-18R). The binding of ligands induces conformational changes in the receptor complexes, allowing for downstream signaling initiation.
2. Recruitment of Signaling Molecules: Upon ligand binding, the IL-1 receptor complex recruits signaling molecules, including interleukin-1 receptor-associated kinases (IRAKs), through the adaptor protein MyD88 (Myeloid differentiation primary response 88). IRAK4 is initially recruited to the receptor complex, followed by the recruitment and activation of IRAK1 and IRAK2.
3. IRAK Activation and Complex Formation: IRAK4 phosphorylates IRAK1, leading to its dissociation from the receptor complex. The phosphorylated IRAK1 then forms a complex with TRAF6 (TNF receptor-associated factor 6), an adaptor protein. This complex formation is facilitated by additional proteins, including IRAK2 and MyD88.
4. Signal Propagation: The IRAK1-TRAF6 complex acts as a signaling platform, recruiting and activating several downstream signaling molecules, including TGF-β-activated kinase 1 (TAK1), TAK1-binding proteins (TABs), and IκB kinase (IKK) complexes.
5. Activation of NF-κB: The activated IRAK1-TRAF6 complex triggers the activation of IKK complexes, which consist of IKKα, IKKβ, and IKKγ (also known as NEMO). These IKK complexes phosphorylate inhibitor of kappa-B (IκB) proteins, leading to their ubiquitination and subsequent degradation.
6. NF-κB Translocation and Gene Expression: The degradation of IκB releases the NF-κB transcription factors, allowing them to translocate into the nucleus. In the nucleus, NF-κB binds to specific DNA sequences, known as κB sites, and activates the transcription of various genes involved in immune responses, inflammation, and cell survival.
7. Activation of MAPK Pathways: Simultaneously with NF-κB activation, IL-1 family signaling also triggers the activation of MAPK pathways, including extracellular signal-regulated kinases (ERKs), c-Jun N-terminal kinases (JNKs), and p38 MAPKs. This activation occurs through the phosphorylation and activation of MAPK kinases (MKKs) by TAK1, leading to the subsequent phosphorylation and activation of MAPKs.
8. Cellular Responses: The activation of NF-κB and MAPK pathways by IL-1 family signaling leads to the production of pro-inflammatory cytokines, such as IL-6 and TNF-α, as well as chemokines and other inflammatory mediators. These molecules promote immune cell activation, recruitment, and amplification of the inflammatory response.
It's important to note that negative regulators, such as suppressor of cytokine signaling (SOCS) proteins and cytokine-inducible SH2-containing protein (CIS), play a role in fine-tuning and dampening the IL-1 family signaling pathway to prevent excessive inflammation and maintain immune homeostasis.
The detailed mechanism described above provides an overview of the IL-1 family signaling pathway, but it's worth noting that specific variations and interactions may occur depending on the ligand, receptor, and cell type involved.
Fig.1 Common signaling pathway for IL-1 family cytokines. (Xu D, et al., 2019)
IL-1α, IL-1β, IL-18, IL-33, and IL-36 bind to IL-1R family members, recruiting MyD88, IRAK4, TRAF6, which resulted in the activation of NF-κB and MAPK and then promoting the transcription of several inflammatory genes. IL-37 and IL-38 exert anti-inflammatory effects by inhibiting NF-κB and MAPK signaling. IL-1Ra and IL-36 Ra cannot recruit the signaling chain.
Self-balancing of the IL-1 Family
The IL-1 family has evolved to maintain a delicate balance in immune regulation and inflammation. While IL-1 family signaling can promote immune responses and inflammation, there are mechanisms in place to regulate and control its activity. Here are some ways in which the IL-1 family maintains balance:
- Negative Feedback Regulation: The IL-1 family signaling pathway is subject to negative feedback regulation. After activation, downstream signaling events lead to the production of anti-inflammatory molecules, such as IL-1 receptor antagonist (IL-1Ra) and IL-10. IL-1Ra competes with IL-1α and IL-1β for binding to IL-1 receptors, preventing their signaling. IL-10 is an anti-inflammatory cytokine that suppresses pro-inflammatory responses. These molecules help dampen the IL-1-mediated inflammatory signals and restore immune homeostasis.
- Receptor Decoy Mechanism: The IL-1 family includes decoy receptors, such as IL-1 receptor type 2 (IL-1R2), which can bind IL-1α and IL-1β but lack intracellular signaling domains. By sequestering IL-1 ligands, decoy receptors limit their interaction with functional IL-1 receptors and reduce the overall inflammatory signaling.
- Spatial and Temporal Regulation: The expression of IL-1 family ligands and receptors is tightly regulated in a spatial and temporal manner. Their expression can be induced by various stimuli, including pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). This regulation allows for a controlled and context-specific activation of IL-1 family signaling, preventing excessive or prolonged inflammation.
- Cytokine Crosstalk and Balance: The IL-1 family interacts with other cytokines and signaling pathways to maintain balance. For example, IL-1 family members can influence the production and activity of other cytokines, such as TNF-α and IL-6. There is intricate crosstalk between various cytokines and signaling pathways to regulate immune responses and inflammation.
- Cell-Specific Responses: Different cell types can respond differently to IL-1 family signaling, leading to diverse outcomes. For example, IL-1β can induce pro-inflammatory responses in immune cells but has trophic and repair functions in certain tissues. This cell-specific response helps to fine-tune the overall immune and inflammatory response.
Overall, the IL-1 family has evolved mechanisms to balance its signaling and ensure appropriate immune responses while preventing excessive inflammation. The interplay between positive and negative regulators, the presence of decoy receptors, the coordination with other cytokines, and cell-specific responses collectively contribute to maintaining immune homeostasis and minimizing the potential detrimental effects of uncontrolled IL-1 family signaling.
Fig.2 IL-1 Family has evolved to balance itself. (Dinarello CA, 2018)
The IL-1 Family provides innate inflammation that is required for non-specific host defense as well as acquired immunity. Inflammation non-specifically contributes to host defense by increasing core temperature, white blood cell infiltration, and microbial killing. Acquired immunity specifically contributes to host defense by acting as an adjuvant for T cells and B cells. Runaway inflammation and autoreactive T-cell activity is controlled by IL-1 Family members IL-1Ra, IL-36Ra, IL-37, IL-38, and IL-18BP.
Creative BioMart is committed to helping you achieve your scientific goals and make meaningful contributions to the study of the mechanisms of action of the various components of the IL-1 family and their role in disease. Contact us today to learn more about our products and resources.
Related References:
- Dinarello CA. Introduction to the interleukin-1 family of cytokines and receptors: Drivers of innate inflammation and acquired immunity. Immunol Rev. 2018;281(1):5-7.
- Kaneko N, Kurata M, Yamamoto T, Morikawa S, Masumoto J. The role of interleukin-1 in general pathology. Inflamm Regen. 2019;39:12.
