RESUMO
CD40 ligand (CD40L) and B-cell activating factor (BAFF) play important roles in the function of B cells. However, the difference of their regulatory effects remains obscure. In this study, we used anti-CD40 to imitate CD40L and investigated the different regulatory effects of CD40L and BAFF on the function of B cells. In the functional analyses, both anti-CD40 and BAFF significantly enhanced the survival and differentiation of B cells, and slightly increased the activation and proliferation. However, in the transcriptome analysis, anti-CD40 and BAFF exerted very different regulation on the gene expression profile of B cells. Anti-CD40 upregulated the expression of genes related to the adaptive immune function of B cells, but BAFF enhanced the genes associated with the innate immune function. Furthermore, the effect analysis of the combination of anti-CD40 or BAFF with anti-IgM also demonstrated that anti-CD40 could cooperate with anti-IgM to promote the proliferation of B cells, but BAFF could not do it. The mechanism study revealed that the different effects of anti-CD40 and BAFF on B cells were resulting from the different modulation on NF-кB, ERK1/2, and PI3K-AKT signaling pathways. Collectively, the results suggest that CD40L mainly promotes adaptive immune function of B cells, but BAFF primarily enhances innate immune function.
Assuntos
Anticorpos/farmacologia , Fator Ativador de Células B/farmacologia , Linfócitos B/efeitos dos fármacos , Antígenos CD40/antagonistas & inibidores , Ligante de CD40/metabolismo , Imunidade Adaptativa/efeitos dos fármacos , Animais , Linfócitos B/imunologia , Linfócitos B/metabolismo , Antígenos CD40/metabolismo , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Imunidade Inata/efeitos dos fármacos , Ativação Linfocitária/efeitos dos fármacos , Masculino , Camundongos Endogâmicos BALB C , Transdução de Sinais , Baço/citologia , TranscriptomaRESUMO
Berkeleyacetal C (BAC), a meroterpenoid compound, was isolated from the fungus Penicillium purpurogenum MHZ 111 and showed favorable activity of inhibiting nitrogen oxide (NO) production of macrophages stimulated by lipopolysaccharide (LPS) in our preliminary screening. In order to develop novel therapeutic drug for acute and chronic inflammatory diseases, the anti-inflammatory activity and underlying mechanisms of BAC were investigated in macrophages and neutrophils. The results showed that BAC significantly inhibited the expression of inducible nitric oxide synthase (iNOS) and the following NO production by macrophages. The expression and secretion of key pro-inflammatory factors and chemokines, including tumor necrosis factor-α (TNF-α)ï¼interleukin-6 (IL-6), interleukin-1ß (IL-1ß), macrophage inflammatory protein-1α (MIP-1α), and monocyte chemotactic protein-1 (MCP-1) were also intensively suppressed by BAC. Furthermore, BAC also markedly inhibited activation of neutrophils and reactive oxygen species production. In mechanism study, BAC selectively suppressed phosphorylation of nuclear factor-κB (NF-κB), extracellular signal-regulated protein kinases 1 and 2 (ERK1/2), and interferon regulatory transcription factor 3 (IRF3) during the activation of NF-κB, mitogen-activated protein kinase (MAPK), signal transducer and activator of transcription 1 and 3 (STAT1/3), and IRF3 signaling pathways induced by LPS. In summary, BAC exerts strong anti-inflammatory effects by inhibiting NF-κB, ERK1/2 and IRF3 signaling pathways and thereby shows great potential to be developed into therapeutic agent for inflammatory disorders.