Notch Ligand Delta-Like 4-Pretreated Dendritic Cells Alleviate Allergic Airway Responses by Enhancing IL-10 Production

Abstract

The Notch pathway plays a role in the processes of cell proliferation, differentiation, and apoptosis, which affect the development and function of various organs. Dendritic cells (DCs), as professional antigen-presenting cells (APCs), induce T cell activation and promote T cell differentiation by antigen stimulation. Research has shown that Notch ligand delta-like 4 (Dll4) in APCs is associated with stimulation of a Th1-type response. However, the regulatory roles of Dll4 in the activation and function of DCs have yet to be clearly elucidated. In this study, we demonstrated that activation of Dll4-pretreated bone marrow-derived DCs by performing ovalbumin (OVA) stimulation expressed a high level of interleukin (IL)-10 without diminishing IL-12 production. By contrast, the proinflammatory cytokines, IL-1β, IL-6, and tumor necrosis factor (TNF)-α, decreased in Dll4-pretreated DCs by performing either lipopolysaccharide (LPS) or OVA stimulation. Compared to fully mature DCs, lower levels of MHC class II CD40 and higher levels of CD80 and CD86 molecules were expressed in these semi-mature like DCs. Dll4 Notch signaling also enhanced Notch ligand mRNA expression of Dll1, Dll4, and Jagged1 in DCs. Dll4-modified DCs exhibited a reduced capacity to stimulate the proliferation of OVA-specific CD4+ T cells, but actively promoted large amounts of IL-10 production in these activated T cells. Furthermore, immunomodulatory effects of Dll4-modified DCs were examined in an established asthmatic animal model. After adoptive transfer of OVA-pulsed plus Dll4-pretreated DCs in OVA-immunized mice, OVA challenge induced lower OVA-specific immunoglobulin E (IgE) and higher IgG2a antibody production, lower eotaxin, keratinocyte-derived chemokine (KC), IL-5, and IL-13 release in bronchial alveolar lavage fluid, attenuated airway hyper-responsiveness, and promoted higher IL-10 and interferon (IFN)-γ production in the spleen. In summary, our findings elucidate the new role of Dll4 in the phenotype and function of DCs and provide a novel approach for manipulating T cell-driven deleterious immune diseases.

Ferulic Acid Induces Th1 Responses by Modulating the Function of Dendritic Cells and Ameliorates Th2-Mediated Allergic Airway Inflammation in Mice

“…At 24 h after the final aerosol OVA exposure, in vivo lung function was measured by detecting changes in airway resistance in response to increasing doses of aerosolized methacholine (MCh, Sigma-Aldrich) in anesthetized mice as described previously [ 14 ]. MCh aerosol was generated with a nebulizer and administrated directly through the ventilator for 3 minutes.…”

Bone marrow transplant-induced alterations in Notch signaling promote pathologic Th17 responses to γ-herpesvirus infection

“…Notch ligand expression on CD11c+ APCs has been implicated in modulating T-cell activation and cytokine production during a variety of disease states and immunological maladies 31 – 35 . To determine whether levels of Notch ligands were altered on APCs following BMT and viral infection, total CD11c+ cells were isolated by magnetic bead separation from either control or BMT mouse groups and infected ex-vivo at a multiplicity of infection of 1.0 for 24 h with γHV-68.…”

Notch Signaling Pathway Was Involved in Regulating Programmed Cell Death 1 Expression during Sepsis‐Induced Immunosuppression

“…Recent studies noted the interaction between them: PD-1 could enhance IL-10 production [ 26 ] and IL-10 also induced PD-1 expression in monocytes and CD4 + T cells [ 27 ]. Additionally, previous research showed that DC matured by Jagged1 (Jgd1-conditioned DC) produced the high level of IL-10 through TLR (via LPS) signaling [ 28 ]. However, whether the Notch signaling pathway in regulation of PD-1 expression is through the IL-10 during sepsis-induced immunosuppression is unclear.…”