IL1A

Interleukin-1 alpha (IL-1α) is a proinflammatory cytokine that belongs to the IL-1 cytokine family. The IL1A gene encodes the protein and is located on chromosome 2 in humans. IL-1α is produced as a 31 kilodalton precursor (pro-IL-1α) that can be proteolytically processed to a 17 kDa mature form; however, the pro-form is biologically active in many contexts. IL-1α is expressed by a variety of cell types, including monocytes, macrophages, keratinocytes, and epithelial cells, and can act locally at sites of tissue injury.

IL-1α exerts its effects by binding to the IL-1 receptor type I (IL-1R1) in conjunction with the IL-1 receptor accessory protein (IL-1RAcP). This triggers intracellular signaling through the MyD88 adaptor, leading to activation of NF-κB and MAP kinases and induction of inflammatory genes, fever, and leukocyte recruitment. The IL-1 receptor type II (IL-1R2) can act as a decoy receptor, limiting signaling. IL-1α has overlapping and distinct roles compared with IL-1β.

Unlike IL-1β, whose maturation depends on caspase-1, IL-1α can be active in its pro-form and can be released actively by cells or passively during necrosis. Calpain-mediated cleavage can generate more potent forms in some contexts. IL-1α is also released as an alarmin in response to cell damage, contributing to sterile inflammatory responses.

Clinical significance: IL-1α participates in numerous inflammatory and autoinflammatory conditions, including rheumatoid arthritis, gout, psoriasis, and skin diseases, as well as in tissue damage from sterile injury. Therapeutic strategies to dampen IL-1 signaling, such as anakinra (an IL-1 receptor antagonist) and rilonacept (an IL-1 trap), reduce inflammation. Canakinumab, an anti-IL-1β antibody, can alleviate symptoms driven by IL-1β, while therapies specifically targeting IL-1α are under investigation.

IL-1α participates in the broader IL-1 cytokine family and interacts with the same receptor system as IL-1β. Regulation occurs at transcriptional and post-translational levels in response to pathogens and tissue damage, reflecting its dual role as a cytokine and an alarmin in immune responses.