RESUMO
Glucocorticoid-induced leucine zipper (GILZ) mimics many of the anti-inflammatory effects of glucocorticoids, suggesting it as a point of therapeutic intervention that could bypass GC adverse effects. We previously reported that GILZ down-regulation is a feature of human SLE, and loss of GILZ permits the development of autoantibodies and lupus-like autoimmunity in mice. To further query the contribution of GILZ to protection against autoimmune inflammation, we studied the development of the lupus phenotype in Lyn-deficient (Lyn-/-) mice in which GILZ expression was genetically ablated. In Lyn-/- mice, splenomegaly, glomerulonephritis, anti-dsDNA antibody titres and cytokine expression were exacerbated by GILZ deficiency, while other autoantibody titres and glomerular immune complex deposition were unaffected. Likewise, in patients with SLE, GILZ was inversely correlated with IL23A, and in SLE patients not taking glucocorticoids, GILZ was also inversely correlated with BAFF and IL18. This suggests that at the onset of autoimmunity, GILZ protects against tissue injury by modulating pro-inflammatory pathways, downstream of antibodies, to regulate the cycle of inflammation in SLE.
Assuntos
Citocinas/genética , Regulação da Expressão Gênica , Mediadores da Inflamação/metabolismo , Fatores de Transcrição/metabolismo , Animais , Complexo Antígeno-Anticorpo/efeitos adversos , Complexo Antígeno-Anticorpo/imunologia , Autoanticorpos/imunologia , Biomarcadores , Citocinas/metabolismo , Modelos Animais de Doenças , Suscetibilidade a Doenças , Imuno-Histoquímica , Lúpus Eritematoso Sistêmico/etiologia , Lúpus Eritematoso Sistêmico/metabolismo , Lúpus Eritematoso Sistêmico/patologia , Nefrite Lúpica/etiologia , Nefrite Lúpica/metabolismo , Nefrite Lúpica/patologia , Camundongos , Camundongos Knockout , Especificidade de ÓrgãosRESUMO
Macrophage migration inhibitory factor (MIF) is a pleiotropic inflammatory molecule with both cytokine and noncytokine activity. MIF is constitutively released from multiple cell types via an unconventional secretory pathway that is not well defined. Here, we looked at MIF release from human and mouse monocytes/macrophages in response to different stimuli. While MIF release was not significantly altered in response to lipopolysaccharide or heat-killed Escherichia coli, cytotoxic stimuli strongly promoted release of MIF. MIF release was highly upregulated in cells undergoing necrosis, necroptosis and NLRP3 inflammasome-dependent pyroptosis. Our data suggest that cell death represents a major route for MIF release from myeloid cells. The functional significance of these findings and their potential importance in the context of autoimmune and inflammatory diseases warrant further investigation.
