Pepijn van Houten1, Annenienke van de Ven2, Mihai Netea3, Antonius van Herwaarden4, Martin Jaeger5, Romana Netea-Maier6
(1) Department of Internal Medicine, Division of Endocrinology, Radboud University Medical Center, Nijmegen, The Netherlands. (2) Department of Internal Medicine, Division of Endocrinology, Radboud University Medical Center, Nijmegen, The Netherlands. (3) Department of Internal Medicine, Radboud Community for Infectious Diseases, Radboud Univeristy Medical Center, Nijmegen, the Netherlands. (4) Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, The Netherlands. (5) Department of Internal Medicine, Division of Endocrinology, Radboud University Medical Center, Nijmegen, The Netherlands. (6) Department of Internal Medicine, Division of Endocrinology, Radboud University Medical Center, Nijmegen, The Netherlands.
Introduction
Endogenous Cushing’s syndrome (CS) is characterized by chronic hypercortisolism. After achieving remission, the incidence of several comorbidities, including cardiovascular diseases and malignancies, remains increased and quality of life remains impaired. Moreover, the incidence of inflammatory disorders increases after curation of CS. We previously described how the innate immune cell function is suppressed in patients with active CS. 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.
Methods
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 ex vivo stimulation were compared between diagnosis and after achieving remission. Changes in circulating inflammation-related proteins were assessed by proximity extension assay proteomics and ELISA.
Results
After achieving remission of CS, we found higher percentages of lymphocytes and lower percentages of monocytes, which was a shift towards the situation in healthy persons. Production of pro-inflammatory cytokines IL-6 and IL-8 by monocytes after 24 hours 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 C-reactive protein did not change after remission.
Conclusion
After achieving remission of CS, patients display increased pro-inflammatory cytokine production by monocytes and persistent systemic inflammation. This could partially explain why they are prone to inflammatory disorders.