Increased cytokine production capacity and persistent inflammation after achieving remission of Cushing’s syndrome

Endogenous Cushing’s syndrome (CS) is characterized by chronic hypercortisolism. After achieving remission, morbidity remains increased and quality of life remains impaired. Moreover, the incidence of inflammatory disorders increases after remission of CS. Despite these immune-mediated clinical consequences, the course of innate immune cell function after remission of CS is poorly known. In this study we aimed to assess changes in innate immune cell function and systemic inflammatory markers after achieving remission of CS. Blood samples were collected from nine CS patients (six adrenal CS and three Cushing’s disease) at diagnosis and after achieving remission and fully tapering off glucocorticoid suppletion. Peripheral blood mononuclear cell (PBMC) cellularity and monocyte-derived cytokine responses upon 24 h of ex vivo stimulation were compared between at diagnosis and after achieving remission. Changes in circulating inflammation-related proteins were assessed by proximity extension assay proteomics and ELISA. After achieving remission of CS, the PBMC fraction showed higher percentages of lymphocytes and lower percentages of monocytes. Production of pro-inflammatory cytokines IL-6 and IL-8 by monocytes after 24 h of stimulation with microbial stimuli was higher after achieving remission, while production of anti-inflammatory cytokines IL-10 and IL-1Ra was lower. Proteomic analysis of plasma identified seven inflammation-related proteins with increased expression and eleven proteins with decreased expression after achieving remission. Concentrations of circulating IL-6, IL-8 and CRP did not change after remission. In conclusion, increased pro-inflammatory cytokine production by monocytes and persistent systemic inflammation could partially explain increased morbidity and incidence of inflammatory disorders after achieving remission of CS.