Extracellular signal–regulated protein kinase signaling pathway negatively regulates the phenotypic and functional maturation of monocyte-derived human dendritic cells

Abstract

IntroductionDendritic cells (DC) are professional antigen-presenting cells that are critically involved in the initiation of T cell-dependent immune responses as a consequence of their high expression of major histocompatibility complex (MHC) and costimulatory molecules. 1 DC are sparsely distributed throughout the body and, in most tissues, are present in an immature state, showing a high capacity for antigen uptake and processing but unable to stimulate T cells. 1,2 Once activated by inflammatory stimuli or infectious agents, DC undergo a maturation process whose hallmarks are up-regulated expression of costimulatory (CD40, CD80, and CD86) and adhesion (CD54 and CD58) molecules, migration into lymphoid organs, and subsequent acquisition of the capacity to activate quiescent, naïve, and memory lymphocytes. [1][2][3][4] In vitro, DC can be derived from either precursor cells or peripheral blood monocytes 5-8 when the appropriate cytokine signals are provided. Immature monocytederived DC (MDDC) can be obtained from peripheral blood monocytes in the presence of granulocyte-macrophage colonystimulating factor (GM-CSF) and interleukin-4 (IL-4). Addition of lipopolysaccharide (LPS) or tumor necrosis factor ␣ (TNF-␣) leads to the appearance of MDDC with all the morphologic, phenotypic, and functional characteristics of mature DC, 5,6 including de novo expression of CD83, 9 up-regulated expression of adhesion and costimulatory molecules, 1-4,10 loss of mannose-receptor-mediated endocytosis, synthesis and release of IL-12, and enhanced antigen presentation capacity. 11 Thus, in vitro maturation of MDDC represents a useful system for analyzing the molecular and functional changes that take place during acquisition of optimal T-cell-stimulating activity by DC.At least 3 distinct mitogen-activated protein kinase (MAPK) signaling cascades exist in mammals, including the extracellular signal-regulated kinase (ERK), the c-Jun N-terminal kinase (JNK), and the p38 MAPK pathways. 12 These kinases are activated by phosphorylation by distinct upstream MAPK kinases. The ERK signaling cascade regulates cell proliferation and differentiation in response to mitogens and growth factors, whereas the JNK and p38 MAPK pathways are preferentially activated by stress-inducing agents. 12 The availability of specific inhibitors for the ERK and p38 MAPK pathways allows evaluation of their respective involvement in cellular responses to extracellular stimuli. The ERK pathway inhibitors PD98059 13 and U0126 14 prevent activation of mitogenactivated protein kinase kinase (MEK) 1/2, 15 upstream activators of ERK 1/2, whereas the pyridinyl imidazole SB203580 inhibits p38 MAPK activity. 15,16 The intracellular signaling pathways implicated in maturation of MDDC are just beginning to be explored. TNF-␣ stimulation of immature MDDC initiates activation of several MAPKs, including For personal use only. on May 11, 2018. by guest www.bloodjournal.org From ERK 2, stress-activated protein kinase-JNK, and p38 MAPK. 10,17,18 Several reports have suggested t...

Differential Regulation of Vitamin D Receptor and Its Ligand in Human Monocyte-Derived Dendritic Cells

“…Consistent with this, blocking IL-10 enhances sustained NF-B activation and maturation of DCs (32). In another example, exposure of immature moDCs to LPS or TNF-␣ in the presence of serum leads to activation of the extracellular signal-regulated protein kinase-signaling pathway which is a negative regulator of DC maturation (33). These potential autoregulatory phenomena and the work in this study suggest that as DCs integrate positive proinflammatory signals inducing maturation, they simultaneously begin to generate negative signals that limit the extent to which they or other developing DCs can propagate an immune response.…”

Exogenous heat shock protein 27 uniquely blocks differentiation of monocytes to dendritic cells

“…If the MO?iDC differentiation effects of HSP-27 treatment were directly activating MO, then p38 activation might also play a role beyond its requirement for IL-10 induction. Activation of p38 MAP kinase can affect MO differentiation to iDC and is also important in induction of maximal MU function [34,[42][43][44]. Consequently p38 activation might be key in the dual MO?DC and MO?MU differentiation dysfunction we observed.…”

“…This could be beneficial in cases when HSP-27 release is the result of extensive tissue damage and accompanied by release of degraded self proteins which could trigger auto-immunity. HSP-27 may be part of a natural system of endogenous proteins that return immune responses to quiescence [42,49]. However, HSP-27-mediated inhibition of MO?iDC differentiation and subsequent DC activation of T cells may also be pathologically dampening immune responses to tumor antigens.…”

Targeting of macrophage galactose‐type C‐type lectin (MGL) induces DC signaling and activation

“…It is well known that ERK1,2 pathway profoundly influences DC activity. The effects of ERK1,2 signaling on maturation of DCs are highly variable and dependent on the type of stimulus added to the cells, even if it appears to negatively regulate the phenotypic and functional maturation of DCs [39]. On the other hand, the activation of NF-κB signal is essential for DC development and survival and has a high impact on DC maturation and in the production of proinflammatory cytokines, such as IL-12, IL-6, TNF-α, and IFN-α/β [23,40].…”