The studies were performed by Eli Menkin and Paul Beeson in 1943–1948 on the fever-producing properties of proteins released from rabbit peritoneal exudate cells.

[1] The basis for the term "interleukin" was to streamline the growing number of biological properties attributed to soluble factors from macrophages and lymphocytes.

At the time of the assignment of these names, there was no amino acid sequence analysis known and the terms were used to define biological properties.

In 1985 two distinct, but distantly related complementary DNAs encoding proteins sharing human IL-1 activity were reported to be isolated from a macrophage cDNA library, thus defining two individual members of the IL-1 family – IL-1α and IL-1β.

IL-1 family precursors do not have a clear signal peptide for processing and secretion and none of them are found in the Golgi; they belong to so-called leaderless secretory protein group.

But this is not a common feature for all IL-1 family members, since IL-1β and IL-18 precursor forms do not bind their receptors and require proteolytic cleavage by either intracellular caspase-1 or extracellular neutrophilic proteases.

According to that, they suggested that IL-1F6, IL-1F8 and IL-1F9 should get new names IL-36α, IL-36β and IL-36γ, even though they are encoded by distinct genes, they use the same receptor complex IL-1Rrp2 and coreceptor IL-1RAcP and deliver almost identical signals.

[5][17] IL-1α or IL-1β bind first to the first extracellular chain of IL-1RI, that recruits the IL-1 receptor accessory protein (IL-1RAcP), which serves as a coreceptor and is necessary for signal transduction and it is also needed for activation of IL-1RI by IL-18 and IL-33.

They are called the myeloid differentiation primary response gene 88 (MYD88) and interleukin-1 receptor-activated protein kinase (IRAK) 4.

[17] These signaling pathways lead to activation of many transcription factors, such as NF-κB, AP-1, c-Jun N-terminal kinase (JNK) and p38 MAPK.

In contrast, monocytes and macrophages do not contain preformed IL-1α precursors, but instead rely on de novo synthesis.

Processing liberates the 16-kDa N-terminal propiece cleavage product (ppIL-1α), which contains a nuclear localization sequence (NLS), and translocates to the nucleus, functioning as a transcription factor.

The precursor form of IL-1α, which has both the N-terminal and C-terminal receptor interacting domains, acts as a damage-associated molecular pattern (DAMP) molecule.

Cell stress could be due to infection, injury, ischemia, hypoxia, acidosis and complement lysis.

IL-1α also stimulates transcription and secretion of IL-1β from monocytes, so the initiator of immune responses is likely IL-1α precursor by induction of neutrophil infiltration.

Its expression is induced by transcription factor NF-κB after exposure of innate immune cells to alarmins.

This occurs, for instance, after exposure of macrophages and dendritic cells to lipopolysaccharide (LPS), which binds to TLR4 and acts as pathogen-associated molecular pattern, which is another group of alarmins.

Caspase-1 needs to be activated by a formation called the inflammasome which is mediated by cytoplasmic pattern recognition receptor signaling.

For instance, Rothwell and coworkers reported evidence that Leptin actions on food intake and body temperature are mediated by IL-1 at the level of the CNS (Luheshi GN, Gardner JD, Rushforth DA, Loudon AS, Rothwell NJ: Leptin actions on food intake and body temperature are mediated by IL-1.

Moreover, lack of IL-1RI–mediated biological activity in IL-1 receptor knockout mice causes mature-onset obesity (Garcia M, Wernstedt I, Berndtsson A, Enge M, Bell M, Hultgren O, Horn M, Ahren B, Enerbäck S, Ohlsson C, Wallenius V, Jansson J-O.

IL-1ra is synthesized as a preprotein containing a classical 25 amino acid long signal sequence that allows secretion via the endoplasmic reticulum / Golgi apparatus.

[26] The soluble form is produced by hepatocytes and regulated by pro-inflammatory cytokines (IL1-β and a combination of IL1-β and IL-6) and other acute phase proteins.

[35] IL-33 is synthesized as a 31-kDa precursor form and binds the ST2 receptor and IL-1RAcP coreceptor, which stimulates signaling that activates transcription factors as NF-κB and ERK, p38 and JNK MAPKs.

On the other hand, the mature forms IL-3395-270, IL-3399-270 and IL-33109-270, which are processed from a precursor by serine proteases cathepsin G and elastase, are even more potent activators of inflammatory responses.

[39] IL-36β is expressed in the tonsils, bone marrow, heart, placenta, lung, testes, intestine, monocytes and B-lymphocytes.

[39] IL-36ra is highly expressed by keratinocytes, in psoriatic skin, placenta, uterus, brain, kidneys, monocytes, B-lymphocytes and dendritic cells.

[49] Polymorphisms in IL-1 genes have been found to contribute to genetic susceptibility to some cancers,[51] ankylosing spondylitis,[52] and Graves' disease.

[53] In terms of clinical use, because of its characterization as a hematopoietic factor, IL-1 was given to patients after bone marrow transplantation to improve the engraftment.

The endogenous IL-1 receptor antagonist (IL-1Ra), also known as anakinra, was tried in clinical trials to lessen systemic inflammation, but did not demonstrate a statistically significant difference from placebo.

Anakinra (IL-1Ra) is FDA-approved as a therapy for patients with rheumatoid arthritis,[54] because it reduces symptoms and slows joint destruction of this inflammatory disease.