Immunosuppressive dendritic and regulatory T cells are upregulated in melanoma patients.

Background: Immunologic therapies for melanoma rarely succeed, suggesting a persistent counter-regulatory immune modulation. Regulatory T cells (T(regs)) and plasmacytoid subpopulations of dendritic cells (pDCs) inhibit the immune response. We hypothesize that melanoma upregulates T(regs )and subpopulations of immunosuppressive dendritic cells (DCs).

Melanoma skews dendritic cells to facilitate a T helper 2 profile.

Background: Patients with progressing melanoma have a circulating cytokine profile reflecting a T helper cell type 2 (Th2) imbalance, while patients responding to therapy favor a Th1 profile. The aim of this study was to determine the role of circulating dendritic cells (DCs) in mediating this imbalance.

Methods: Isolated human peripheral blood mononuclear cells (PBMCs) were exposed to cell-free melanoma-conditioned medium (MCM) or control fibroblast-conditioned medium before stimulation.

Phosphoinositide 3-kinase and Akt occupy central roles in inflammatory responses of Toll-like receptor 2-stimulated neutrophils.

Neutrophils are critical initiators and effectors of the innate immune system and express Toll-like receptor 2 (TLR2) and TLR4. Although signaling through pathways involving phosphoinositide 3-kinase (PI3-K) and the downstream kinase Akt (protein kinase B) plays a central role in modulating neutrophil chemotaxis and superoxide generation in response to engagement of G protein-coupled receptors, the importance of these kinases in affecting inflammatory responses of neutrophils stimulated through TLR2 has not been examined. In these experiments, we found activation of Akt in neutrophils stimulated with the TLR2-specific ligands peptidoglycan and the lipopeptide tri-palmitoyl-S-glyceryl-Cys-Ser-(Lys)(4) that occurred earlier and was of greater magnitude than that present after exposure to the TLR4 agonist LPS.

Modulation of bone marrow-derived neutrophil signaling by H2O2: disparate effects on kinases, NF-kappaB, and cytokine expression.

Reactive oxygen species (ROS), including hydrogen peroxide (H2O2), are generated in increased amounts in pathological, biological processes and can play a role in signal transduction. Neutrophils often accumulate in acute inflammatory reactions, at sites where elevated concentrations of ROS are present. ROS have been demonstrated to participate in the activation of intracellular signaling pathways, including those involved in modulating nuclear accumulation and transcriptional activity of NF-kappaB.