Impaired expression of the TWIK2 channel leads to reduced IL-1 family cytokine production in patients with nontuberculous mycobacterial lung disease

Abstract Nontuberculous mycobacteria (NTM) cause pulmonary disease in individuals without obvious immunodeficiency. This study was initiated to gain insight into the immunological factors that predispose persons to NTM pulmonary disease (NTMPD). Blood was obtained from 15 pairs of NTMPD patients and their healthy household contacts. Peripheral blood mononuclear cells (PBMCs) were stimulated with the M. avium complex (MAC). A total of 34 cytokines and chemokines were evaluated in plasma and PBMC culture supernatants using multiplex immunoassays, and gene expression in the PBMCs was determined using real-time PCR. PBMCs from NTMPD patients produced significantly less interleukin (IL)-1β, IL-18, IL-1α and IL-10 than PBMCs from their healthy household contacts in response to MAC. Although plasma RANTES levels were high in NTMPD patients, they had no effect on IL-1β production by macrophages infected with MAC. TLR2 and TWIK2 were impaired in response to MAC in PBMCs of NTMPD patients. A TLR2 inhibitor decreased all 4 cytokines, whereas a TWIK2 inhibitor decreased the production of IL-1β, IL-18, and IL-1α, but not IL-10, by MAC-stimulated PBMCs and monocytes. We suggest that an attenuated TWIK2-mediated IL-1 response may increase susceptibility to NTM pulmonary infection.