Autor(es):
Lemos, Henrique Paula ; Grespan, Renata ; Manfredo Vieira, Silvio ; Cunha, Thiago Mattar ; Verri, Waldiceu A. ; Fernandes, Karla S. ; Souto, Fabrício Oliveira ; McInnes, Iain B. ; Ferreira, Seérgio Henrique ; Liew, Foo Y. ; Cunha, Fernando Queiroz
Data: 2020
Origem: Oasisbr
Assunto(s): 3 [3 Tert Butylthio 1 (4 Chlorobenzyl) 5 Isopropyl 2 Indolyl] 2,2 Dimethylpropionic Acid; Etoricoxib; Gamma Interferon; Indometacin; Interleukin-12; Interleukin-17; Interleukin-23; Prostaglandin; Prostaglandin Synthase Inhibitor; Tumor Necrosis Factor Alpha Antibody; Animals Cell; Animals Experiment; Animals Model; Animals Tissue; Arthritis; Cell Migration; Controlled Study; Female; Male; Mouse; Neutrophil; Neutrophil Chemotaxis; Nonhuman; Pathogenesis; Priority Journal; Protein Expression; Protein Function; Animal; Arthritis, Rheumatoid; Cyclooxygenase Inhibitors; Dinoprostone; Inflammation; Interferon-gamma; Interleukin-12; Interleukin-17; Interleukin-23; Mice; Neutrophil Infiltration; Prostaglandins; Murinae; Mus
Descrição
IL-23/IL-17-induced neutrophil recruitment plays a pivotal role in rheumatoid arthritis (RA). However, the mechanism of the neutrophil recruitment is obscure. Here we report that prostaglandin enhances the IL-23/IL-17-induced neutrophil migration in a murine model of RA by inhibiting IL-12 and IFN γ production. Methylated BSA (mBSA) and IL-23-induced neutrophil migration was inhibited by anti-IL-23 and anti-IL-17 antibodies, COX inhibitors, IL-12, or IFNy but was enhanced by prostaglandin E2 (PGE2). IL-23-induced IL-17 production was increased by PGE2 and suppressed by COX- inhibition or IL-12. Furthermore, COX inhibition failed to reduce IL-23-induced neutrophil migration in IL-12- or IFNγ-deficient mice. IL-17-induced neutrophil migration was not affected by COX inhibitors, IL-12, or IFNγ but was inhibited by MK886 (a leukotriene synthesis inhibitor), anti-TNFα, anti-CXCL1, and anti-CXCL5 antibodies and by repertaxin (a CXCR1/2 antagonist). These treatments all inhibited mBSA- or IL-23-induced neutrophil migration. IL-17 induced neutrophil chemotaxis through a CXC chemokines-dependent pathway. Our results suggest that prostaglandin plays an important role in IL-23-induced neutrophil migration in arthritis by enhancing IL-17 synthesis and by inhibiting IL-12 and IFNγ production. We thus provide a mechanism for the pathogenic role of the IL-23/IL-17 axis in RA and also suggest an additional mechanism of action for nonsteroidal anti-inflammatory drugs.
