Interleukin-1 (IL-1) comprises a family of cytokines implicated in the pathophysiology of many respiratory disorders. This family includes pro-inflammatory IL-1α and IL-1β and anti-inflammatory IL-1 receptor antagonist (IL-1Ra) – all of which have a role in the innate immune response to a pathogen or injury. While IL-1β is the primary driver of inflammation, IL-1Ra has an anti-inflammatory role that moderates the risk of excessive response.
IL-1 Drives Innate Immunity
The IL-1 family has a leading role in the innate immune system where it provides an early response to infection or tissue damage and regulates functions of the adaptive immune response. The key agonists, IL-1α and IL-1β, bind to the IL-1 receptor and promote a multi-step inflammatory process that includes expression of pro-inflammatory IL-6 and IL-8. The process is particularly important in the body’s defense against intracellular pathogens. While typically protective, the inflammatory response, if unchecked, can lead to tissue damage.
Cytokine Storm Syndrome is a hyper-immune response caused by an excessive or uncontrolled release of proinflammatory cytokines. While the etiology of Cytokine Storm Syndrome is unknown, it has been shown to be a driver of acute respiratory failure and can be lethal. Patients who do survive manifest varying degrees of pulmonary fibrosis and restrictive ventilatory impairment.
IL-1Ra, the only antagonist in the IL-1 family, binds competitively to the same IL-1R1 receptor as does IL-1α and IL-1β. Importantly, IL-1Ra does not generate the conformational change that would produce proinflammatory chemokines (Borthwick 2015). In this way, IL-1Ra can attenuate the inflammation mediated by IL-1α and IL-1β and lead to a resolution of the inflammatory response.
IL-1Ra and Bronchiolitis obliterans syndrome (BOS)
Bronchiolitis obliterans syndrome (BOS) remains the major cause of allograft dysfunction following lung transplantation and is associated with poor long-term survival. It may be considered as a form of chronic transplant rejection and manifests as an obstructive pattern on pulmonary functions testing. BOS is the leading cause of death in lung transplant recipients who survive beyond one year and can be found in more than 50% of patients who are alive at 5 years. To date, no effective treatment exists for BOS.
Bronchiolitis obliterans syndrome is characterized by increased IL-1 production and subsequent over-activation of the innate immune response in lung tissue. Treatment with inhaled IL-1Ra has demonstrated the potential to attenuate the innate immune response and improve or prevent further loss of respiratory function.