TY - JOUR
T1 - Differential role of MAPK signaling in human dendritic cell maturation and Th1/Th2 engagement
AU - Nakahara, Takeshi
AU - Moroi, Yoichi
AU - Uchi, Hiroshi
AU - Furue, Masutaka
N1 - Funding Information:
The phenotypic and functional observations described in the preceding sections indicate that (1) p38 MAPK, JNK, and ERK differentially regulate the maturation pathway of MoDCs, (2) p38 MAPK is essential in achieving professional immunostimulatory function, and (3) the incomplete inhibition of DC maturation by JNK inhibitor (SP600125) is insufficient for down-regulating the allostimulatory function of DCs. However, various maturation stimuli activate these three MAPKs at the same time during MoDC maturation. What is the point in activating all three MAPKs together? Agrawal et al. reported that distinct TLR agonists differentially modulate p38 MAPK and ERK activity, as well as cytokine responses in DCs, to stimulate different Th responses ). In addition, we reported that JNK inhibitor-pretreated MoDCs might skew the immune response toward a Th2 differentiation via inhibition of IL-12 p70 production [21] . Escherichia coli LPS and flagellin, which trigger TLR4 and TLR5 respectively, instruct DCs to stimulate Th1 responses via IL-12 p70 production. The IL-12 p70 production depends on the phosphorylation of p38 MAPK and JNK1/2. In contrast, the TLR2 agonist (Pam3cys) and a Th2 stimulus such as schistosome egg antigen barely induce production of IL-12 p70, yet they stimulate a sustained duration and increased magnitude of ERK phosphorylation which results in a Th2 bias ( Fig. 3 [23] . Thus, p38 MAPK and JNK may be closely linked to Th1 differentiation and ERK may be linked to Th2 differentiation via modulation of properties, especially IL-12 production of MoDCs. Previously it was reported that the quality of immune response depends on the subset of DCs. ). [45] Many observations suggested that distinct DC subsets might indeed regulate Th responses differentially [45] ; specifically, myeloid DCs (DC1) induce a Th1 response and lymphoid DCs (DC2, plasmacytoid DC) induce a Th2 response. In contrast, more recent reports suggest that specific subsets of either murine or human DCs, when cultured in vitro with different stimuli or different TLR ligands, respond with great plasticity of in terms of gene expression and cytokine secretion [46–50] . The key concepts that emerge from these reports are that (1) activation of MoDCs via TLRs or other PRRs does not always result in Th1 responses, but can induce skewing toward Th2 responses and (2) a possible mechanism of mediation of the distinct DC responses triggered by the different stimuli may involve differential modulation of the threshold and duration of MAPK signaling. Thus, various maturation stimuli may control the balance of phosphorylation of the three MAPKs and may develop the distinct DCs that can then induce the optimal immune response for their microenvironment ( Fig. 4 Moreover, MAPKs are emerging as key pharmacological targets and they appear promising for implementation of new therapeutic strategies. Indeed, inhibition of MAPK activation may be an important event within the context of the molecular mechanisms that underlie the anti-inflammatory action of corticosteroids [51] . The immunosuppressive effect of CsA may possibly be attributed, at least in part, to the inhibition of the JNK and p38 pathways [52] . Furthermore, several recent studies suggest that MAPK inhibitors can exert significant therapeutic effects in some experimental models of inflammatory disease [53–55] . This review has pointed out evidence that in addition to the direct effects of MAPK on various cell types, DCs are also the target cells for immunomodulation by MAPK inhibitor. These findings raise the hope that in the near future the therapeutic benefits of selectively modulating MAPK activity may become clinically applicable to the treatment of inflammatory diseases. Masutaka Furue was graduated from School of Medicine, University of Tokyo as MD in 1980, and received PhD from University of Tokyo in 1986. He worked under Dr. Stephen I. Katz as a research fellow in Dermatology Branch, National Institutes of Health, Bethesda, U.S.A. from 1986 to 1988. He was an associate professor, Yamanashi Medical University from 1992 to 1995, and moved to University of Tokyo as an associate professor in 1995. He has been a chairman and professor of Department of Dermatology, Kyushu University since 1997. He was a vice director of Kyushu University Hospital in 2002–2004. His interests are in the areas of atopic dermatitis, cutaneous neoplasms, immunotherapy by dendritic cells and dioxins. He has been the Board of Directors of Japanese Dermatological Association, Board of Directors of Japanese Society for Investigative Dermatology, President of Japanese Society for Cosmetic Dermatology, President of Japanese Dendritic Cell Meeting, Board of Directors of Japanese Pressure Ulcer Association, and Editor of Nishinihon Hifuka. He has also been elected as President of The 10th International Symposium on Dendritic Cells in Fundamental and Clinical Immunology, 2008.
PY - 2006/4
Y1 - 2006/4
N2 - Dendritic cells (DCs) are potent antigen-presenting cells that can stimulate resting T cells in the primary immune response. During the maturation process, immature DCs lose their ability to internalize antigens and they acquire the capacity to present antigens to naive T cells. Many observations have suggested that distinct DC subsets might differentially regulate Th responses. However, recent reports suggest that specific subsets of either murine or human DCs cultured in vitro with different stimuli respond with great plasticity in terms of both gene expression and cytokine secretion. Thus, the microenvironment of DCs may determine the nature of mature DCs and the subsequent immune response. The mechanism by which the character of DCs is determined is unknown. The in vitro maturation process of human monocyte-derived DCs (MoDC) can be initiated by various stimuli. Many stimuli induce phosphorylation of extracellular signal-regulated kinases (ERK), c-Jun N-terminal kinases (JNK), and p38 MAPK in DCs during maturation. Such kinase-specific inhibitors help to reveal the functions of MAPKs in the maturation of human MoDCs. Recent studies suggest that three MAPK signaling pathways differentially regulate all aspects of phenotypic maturation, cytokine production, and functional maturation of MoDCs. Thus, distinct maturation of DCs may be induced by modulating the balance of phosphorylation of the three MAPKs. In this review, we summarize the role of MAPK signaling pathways in the maturation of human MoDCs.
AB - Dendritic cells (DCs) are potent antigen-presenting cells that can stimulate resting T cells in the primary immune response. During the maturation process, immature DCs lose their ability to internalize antigens and they acquire the capacity to present antigens to naive T cells. Many observations have suggested that distinct DC subsets might differentially regulate Th responses. However, recent reports suggest that specific subsets of either murine or human DCs cultured in vitro with different stimuli respond with great plasticity in terms of both gene expression and cytokine secretion. Thus, the microenvironment of DCs may determine the nature of mature DCs and the subsequent immune response. The mechanism by which the character of DCs is determined is unknown. The in vitro maturation process of human monocyte-derived DCs (MoDC) can be initiated by various stimuli. Many stimuli induce phosphorylation of extracellular signal-regulated kinases (ERK), c-Jun N-terminal kinases (JNK), and p38 MAPK in DCs during maturation. Such kinase-specific inhibitors help to reveal the functions of MAPKs in the maturation of human MoDCs. Recent studies suggest that three MAPK signaling pathways differentially regulate all aspects of phenotypic maturation, cytokine production, and functional maturation of MoDCs. Thus, distinct maturation of DCs may be induced by modulating the balance of phosphorylation of the three MAPKs. In this review, we summarize the role of MAPK signaling pathways in the maturation of human MoDCs.
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U2 - 10.1016/j.jdermsci.2005.11.004
DO - 10.1016/j.jdermsci.2005.11.004
M3 - Review article
C2 - 16352421
AN - SCOPUS:33644913374
SN - 0923-1811
VL - 42
SP - 1
EP - 11
JO - Journal of Dermatological Science
JF - Journal of Dermatological Science
IS - 1
ER -