IL-1, as the name implies, was the first interleukin to be identified and characterized in the early '80s. We have known for some time that IL-1 signals by binding to a heterodimeric receptor that combines a so-called primary receptor, IL-1RI, with an accessory receptor, IL-1RAcP. 

The IL-1 family and their receptors has grown over time and, with advancing research, their biological significance is emerging (see Arend, 2008; our earlier 4A update on IL-33). The ligands and their receptors can be clustered into smaller families, each of which includes ligands (IL-1ra, IL-1F7) and/or receptors (IL-1RII, SIGIRR (TIR8)) that act as inhibitory decoys, serving to block signaling in a manner that is likely to be tightly regulated, although the exact details are still being elucidated.

How IL-1 family members interact with their receptors to trigger signaling was unclear until 2010, when Wang and colleagues published the structure of IL-1beta complexed with IL-1RII (a decoy receptor) and IL-1RAcP. The results suggested an unexpected ternary configuration in which the receptor components IL-1RII and IL-1RAcP are orthogonal to each other (right panel, below), contrary to what was believed for growth hormone receptor-like complexes, that the ligand would be central in nucleating the assembly of the two coreceptors (left panel).

Since IL-1RII is a decoy receptor, there was speculation about whether this unusual configuration might be unique to nonsignaling complexes. Further confirmation that it was, in fact, likely to be shared by activating IL-1/receptor complexes was provided in 2012, when our principal consultant, Fernando Bazan, and his colleagues Christoph Thomas and K. Christopher Garcia at Stanford reported the structure of the signaling-competent heterotrimer, IL-1beta/IL-1RI/IL-1RAcp in Nature Structural & Molecular Biology.

"It's reasonable to predict that all members of the IL-1 family will follow this ternary complex paradigm," Fernando postulates, allowing us to develop the model below.

The IL-1 family of ligands and receptors. The eleven known ligands are shown in the outer circle, and bind to primary high-affinity IL-1 receptors (middle circle), which thereupon associate with secondary receptors (inner circle). The inhibitory effect of SIGIRR on IL-1RI and ST2 needs further substantiation. The ligands and coreceptors for IL1RAPL1 and IL1RAPL2  have not been identified to date. Adapted from Thomas et al. (2012).

In summary, this proposed ternary complex paradigm allows us to organize the entire IL-1 system - which also reveals holes that need to be filled in through target discovery, for example to build out the biology of IL-1RAPL1 and -2. These orphan receptors are interesting as they are primarily expressed in the brain, and mutations are associated with X-linked non-syndromic mental retardation mutations. 

"I don't think there are any new alpha receptors remaining to be found," Fernando comments, "so we need to look for CNS expression of one of the existing alpha receptor and piece together the ternary complex. There may, however, be additional unidentified ligands." This pairing exercise could be executed reasonably easily in vitro, but no one's reported any results - maybe because it's primarily of interest to neurobiologists. Another example of scientists in different disciplines not communicating and possibly missing some very interesting biological insights.

The paradigm allows researchers to quickly infer the contact sites between IL-1 family members and their receptors, which may speed drug design. If the history of the IL-1 family is any indication, we have yet to discover new biological with the potential for new therapeutic breakthroughs in the future.