Interleukin1 alpha

Interleukin-1 alpha is a "dual function cytokine", i.e. it plays a role both in the cell nucleus by influencing transcription and extracellularly by exerting receptor-mediated effects as a classical cytokine. IL-1 alpha is synthesized as a precursor protein and is constitutively stored in the cytoplasm of cells of mesenchymal origin and in epithelial cells. In contrast, monocytes and macrophages do not contain preformed IL-1alpha precursor proteins, but rely on de novo synthesis. The IL-1alpha precursor is processed by a Ca2+-activated protease, calpain, to its mature 17-kDa form.

Interleukin-1 genes: Interleukin-1alpha(IL1A gene) and interleukin-1beta are encoded by different genes. The sequence homology is less than 26 %, but this homologous region is responsible for the binding of both cytokines to the same receptor of the interleukin-1 family, namely interleukin-1R1. Since both cytokine variants bind to the same receptor, interleukin-1alpha and interleukin-1beta cause the same inflammatory responses.

Interleukin-1 alpha also stimulates the transcription and secretion of interleukin-1beta from monocytes, so that the trigger of the immune responses is probably an interleukin-1 alpha precursor that induces the infiltration of neutrophils. Interleukin-1beta appears to be an amplifier of inflammation through the recruitment of macrophages in the context of sterile inflammation (Sahoo M et al. 2011; Matzinger P 2012)

Upon activation of interleukin-1alpha, the N-terminal 16-kDa cleavage product (ppIL-1 alpha) is released, which contains a nuclear localization sequence (NLS), migrates to the nucleus and functions as a transcription factor. The precursor form of IL-1alpha, which has both the N-terminal and C-terminal receptor-interacting domains, functions as a damage-associated molecular pattern(DAMP) molecule. DAMPs, also known as alarmins, are recognized by cells of innate immunity through pattern recognition receptors (PRRs) and act as danger signals for the immune system. DAMPs are generally released by stressed cells undergoing necrosis or pyroptosis. Their intracellular components are released into the extracellular space. Due to the misfolding or oxidative changes of these molecules in connection with the altered pH value, they can be recognized and processed by the innate immune system as "pathogenic" molecules.

This includes the activation of important transcription factors associated with inflammatory and immune responses, such as nuclear factor-kB (NF-kB), activator protein-1 (AP-1), c-Jun N-terminal kinase (JNK), p38 and other mitogen-associated protein kinases (MAPKs), extracellular signal-regulated kinases (ERKs) and interferon-regulating genes (Cavalli G et al. 2021). Once activated, these signaling cascades lead to the expression of numerous mediators that together orchestrate the development of an immune response. The most important mechanisms include the synthesis of other cytokines such as interleukin-6, interleukin-2, interferons or various chemokines. chemokines, the production of prostaglandins, vasodilation and the expression of adhesion molecules by endothelial cells that enable the migration of immune cells into the tissue, the activation of T helper cells and the maturation and clonal expansion of B cells that activate adaptive immunity (Cavalli G et al. 2021). In triggering these pro-inflammatory effects, interleukin-1alpha and interleukin-1beta act synergistically with other mediators such as TNFalpha, bradykinin or growth factors. The activation of this interrelated network of soluble and cellular mediators has both local and systemic effects. Local effects are characterized, for example, by inflammation-induced organ dysfunction and ultimately by damage. Systemic effects, on the other hand, include fever, vasodilation (skin rash) and musculoskeletal pain as well as hypotension and shock when concentrations increase (Cavalli G et al. 2021).

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