Together with
IL-12 or
IL-15,
interleukin-18 (IL-18) plays a major role in the production of
interferon-γ from T-cells and natural killer cells; thus,
IL-18 is considered to have a major role in the Th1 response. However, without
IL-12,
IL-18 is proinflammatory in an IFNγ independent manner.
IL-18 is a member of the
IL-1 family of
cytokines and similar to IL-1β, the
cytokine is synthesized as an inactive precursor requiring processing by caspase-1 into an active
cytokine.
IL-18 is also present as an
integral membrane protein but requires caspase-1 for full activity in order to induce IFNγ. Uniquely, unlike IL-1β, the
IL-18 precursor is constitutively present in nearly all cells in healthy humans and animals. The activity of
IL-18 is balanced by the presence of a high-affinity, naturally occurring
IL-18 binding protein (IL-18BP). In humans, increased disease severity can be associated with an imbalance of
IL-18 to IL-18BP such that the levels of free
IL-18 are elevated in the circulation. Increasing number of studies have expanded the role of
IL-18 in mediating
inflammation in animal models of disease using the IL-18BP,
IL-18 deficient mice, neutralization of
IL-18 or deficiency in the
IL-18 receptor alpha chain. A role for
IL-18 has been implicated in several
autoimmune diseases, myocardial function,
emphysema,
metabolic syndromes,
psoriasis,
inflammatory bowel disease,
macrophage activation syndrome,
sepsis and
acute kidney injury, although paradoxically, in some models of disease,
IL-18 is protective. The IL-18BP has been used safely in humans and clinical trials of IL-18BP as well as neutralizing anti-IL-18
antibodies are being tested in various diseases.