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New pro-inflammatory cytokine IL-40 is produced by activated neutrophils and plays a role in the early stages of seropositive rheumatoid arthritis

A. Navrátilová, V. Bečvář, H. Hulejová, M. Tomčík, L. Štolová, H. Mann, O. Růžičková, O. Šléglová, J. Závada, K. Pavelka, J. Vencovský, L. Šenolt, L. Andrés Cerezo

. 2023 ; 9 (2) : . [pub] -

Jazyk angličtina Země Anglie, Velká Británie

Typ dokumentu časopisecké články, práce podpořená grantem

Perzistentní odkaz   https://www.medvik.cz/link/bmc23011511

OBJECTIVE: Interleukin (IL)-40 is a new cytokine related to immune system function and malignancies. Recently, an association of IL-40 with rheumatoid arthritis (RA) and externalisation of neutrophil extracellular traps (NETosis) was found. As neutrophils are implicated in RA development, we investigated IL-40 in early stages of RA (ERA). METHODS: IL-40 was determined in serum of treatment naïve patients with ERA at baseline (n=60) and 3 months after initiation of conventional therapy and in healthy controls (HC; n=60). Levels of IL-40, cytokines and NETosis markers were measured by ELISA. NETosis was visualised by immunofluorescence. In vitro experiments were performed on peripheral blood neutrophils from ERA patients (n=14). Cell-free DNA was analysed in serum and supernatants. RESULTS: Serum IL-40 was elevated in ERA compared with HC (p<0.0001) and normalised after 3 months of therapy (p<0.0001). Baseline serum IL-40 correlated with rheumatoid factor (IgM) (p<0.01), anti-cyclic citrullinated peptide (p<0.01) autoantibodies and NETosis markers (proteinase 3; neutrophil elastase (NE); myeloperoxidase) (p<0.0001). Levels of NE significantly decreased after therapy (p<0.01) and correlated with the decrease of serum IL-40 (p<0.05). In vitro, neutrophils enhanced IL-40 secretion following NETosis induction (p<0.001) or after exposure to IL-1β, IL-8 (p<0.05), tumour necrosis factor or lipopolysaccharide (p<0.01). Recombinant IL-40 up-regulated IL-1β, IL-6 and IL-8 (p<0.05 for all) in vitro. CONCLUSION: We showed that IL-40 is significantly up-regulated in seropositive ERA and decreases after conventional therapy. Moreover, neutrophils are an important source of IL-40 in RA, and its release is potentiated by cytokines and NETosis. Thus, IL-40 may play a role in ERA.

Citace poskytuje Crossref.org

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$a OBJECTIVE: Interleukin (IL)-40 is a new cytokine related to immune system function and malignancies. Recently, an association of IL-40 with rheumatoid arthritis (RA) and externalisation of neutrophil extracellular traps (NETosis) was found. As neutrophils are implicated in RA development, we investigated IL-40 in early stages of RA (ERA). METHODS: IL-40 was determined in serum of treatment naïve patients with ERA at baseline (n=60) and 3 months after initiation of conventional therapy and in healthy controls (HC; n=60). Levels of IL-40, cytokines and NETosis markers were measured by ELISA. NETosis was visualised by immunofluorescence. In vitro experiments were performed on peripheral blood neutrophils from ERA patients (n=14). Cell-free DNA was analysed in serum and supernatants. RESULTS: Serum IL-40 was elevated in ERA compared with HC (p<0.0001) and normalised after 3 months of therapy (p<0.0001). Baseline serum IL-40 correlated with rheumatoid factor (IgM) (p<0.01), anti-cyclic citrullinated peptide (p<0.01) autoantibodies and NETosis markers (proteinase 3; neutrophil elastase (NE); myeloperoxidase) (p<0.0001). Levels of NE significantly decreased after therapy (p<0.01) and correlated with the decrease of serum IL-40 (p<0.05). In vitro, neutrophils enhanced IL-40 secretion following NETosis induction (p<0.001) or after exposure to IL-1β, IL-8 (p<0.05), tumour necrosis factor or lipopolysaccharide (p<0.01). Recombinant IL-40 up-regulated IL-1β, IL-6 and IL-8 (p<0.05 for all) in vitro. CONCLUSION: We showed that IL-40 is significantly up-regulated in seropositive ERA and decreases after conventional therapy. Moreover, neutrophils are an important source of IL-40 in RA, and its release is potentiated by cytokines and NETosis. Thus, IL-40 may play a role in ERA.
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