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Idiopathic pulmonary fibrosis (IPF) is a progressive disease characterized by fibroblast proliferation and excess deposition of collagen and other extracellular matrix (ECM) proteins, which lead to distorted lung architecture and function (1). Given that anti-inflammatory or immunosuppressive therapy currently used for IPF does not improve disease progression therapies targeted to blocking the mechanisms of fibrogenesis are needed (1). Although transforming growth factor-β. (TGF-β) functions are crucial in fibrosis (2,3), antagonizing this pathway in bleomycin-induced pulmonary fibrosis, an animal model of IPF, does not prevent fibrosis completely (4-7), indicating an additional pathway also has a key role in fibrogenesis. Given that the loss of cytosolic phospholipase [A.sub.2] [(cPLA.sub.2)] suppresses bleomycin-induced pulmonary fibrosis (8), we examined the roles of prostaglandins using mice lacking each prostoaglandin receptor (9-15). Here we show that loss of prostaglandin F (PGF) receptor (FP) selectively attenuates pulmonary fibrosis while maintaining similar levels of alveolar inflammation and TGF-β. stimulation as compared to wild-type (WT) mice, and that FP deficiency and inhibition of TGF-β. signaling additively decrease fibrosis. Furthermore, [PGF.sub.2α] is abundant in bronchoalveolar lavage fluid (BALF) of subjects with IPF and stimulates proliferation and collagen production of lung fibroblasts via FP, independently of TGF-β These findings show that [PGF.sub.2α]-FP signaling facilitates pulmonary fibrosis independently of TGF-β and suggests this signaling pathway as a therapeutic target for IPF., [cPLA.sub.2] cleaves phospholipids in response to stimuli and releases arachidonic acid, which is metabolized by cyclooxygenase (COX) to produce prostaglandins and by 5-lipoxygenase to produce leukotrienes. Prostaglandins, including [PGD.sub.2], [PGE.sub.2], [...]

Two distinct helper T ([T.sub.H]) subsets, [T.sub.H]1 and [T.sub.H]17, mediate tissue damage and inflammation in animal models of various immune diseases such as multiple sclerosis, rheumatoid arthritis, inflammatory bowel diseases and allergic skin disorders. These experimental findings, and the implication of these [T.sub.H] subsets in human diseases, suggest the need for pharmacological measures to manipulate these [T.sub.H] subsets. Here we show that prostaglandin [E.sub.2] ([PGE.sub.2]) acting on its receptor EP4 on T cells and dendritic cells not only facilitates [T.sub.H]1 cell differentiation but also amplifies interleukin-23--mediated [T.sub.H]17 cell expansion in vitro. Administration of an EP4-selective antagonist in vivo decreases accumulation of both [T.sub.H]1 and [T.sub.H]17 cells in regional lymph nodes and suppresses the disease progression in mice subjected to experimental autoimmune encephalomyelitis or contact hypersensitivity. Thus, [PGE.sub.2]-EP4 signaling promotes immune inflammation through [T.sub.H]1 differentiation and [T.sub.H]17 expansion, and EP4 antagonism may be therapeutically useful for various immune diseases., Autoaggressive [T.sub.H] cells can induce tissue damage and inflammation and are believed to be crucial in the pathogenesis of various immune diseases (1,2). Recent studies suggest that, among the three [...]

Antigen-specific immune responses in the skin are initiated by antigen uptake into Langerhans cells and the subsequent migration of these cells to draining lymph nodes. Although prostaglandin E[sub.2] (PGE[sub.2]) is produced substantially in skin exposed to antigen, its role remains unclear. Here we show that although Langerhans cells express all four PGE receptor subtypes, their migration to regional lymph nodes was decreased only in EP4-deficient (Ptger4[sup.-/-]) mice and in wild-type mice treated with an EP4 antagonist. An EP4 agonist promoted the migration of Langerhans cells, increased their expression of costimulatory molecules and enhanced their ability to stimulate T cells in the mixed lymphocyte reaction in vitro. Contact hypersensitivity to antigen was impaired in Ptger4[sup.-/-] mice and in wild-type mice treated with the EP4 antagonist during sensitization. PGE[sub.2]-EP4 signaling thus facilitates initiation of skin immune responses by promoting the migration and maturation of Langerhans cells., Author(s): Kenji Kabashima [1, 2]; Daiji Sakata [1]; Miyako Nagamachi [1, 2]; Yoshiki Miyachi [2]; Kayo Inaba [3]; Shuh Narumiya (corresponding author) [1] The skin is exposed to multiple antigens [...]

Innate lymphoid cells (ILCs) are a family of developmentally related leukocytes that rapidly secrete polarized sets of cytokines to combat infection and promote tissue repair at mucosal barriers. Among them, group 3 ILCs (ILC3s) play an important role in maintenance of the gut homeostasis by producing IL-22, and their development and function critically depend on the transcription factor RORγt. Although recent evidence indicates that RORγt+ ILC3s are reduced in the gut in the absence of the Cdc42 activator DOCK8 (dedicator of cytokinesis 8), the underlying mechanism remains unclear. We found that genetic deletion of Dock8 in RORγt+-lineage cells markedly reduced ILC3s in the lamina propria of the small intestine. By analyzing BrdU incorporation, it was revealed that DOCK8 deficiency did not affect the cell proliferation. Furthermore, when lineage marker-negative (Lin–) α4β7+ CD127+ RORγt– fetal liver cells were cultured with OP9 stromal cells in the presence of stem cell factor (SCF) and IL-7 in vitro , RORγt+ ILC3s normally developed irrespective of DOCK8 expression. However, DOCK8-deficient ILC3s exhibited a severe defect in survival of ILC3s under the condition with or without IL-7. Similar defects were observed when we analyzed Dock8 VAGR mice having mutations in the catalytic center of DOCK8, thereby failing to activate Cdc42. Thus, DOCK8 acts in cell-autonomous manner to control survival of ILC3s in the gut through Cdc42 activation. [ABSTRACT FROM AUTHOR]

UV radiation induces systemic immunosuppression. Because nonsteroidal anti-inflammatory drugs suppress UV-induced immunosuppression, prostanoids have been suspected as a crucial mediator of this UV effect. However, the identity of the prostanoid involved and its mechanism of action remain unclear. Here, we addressed this issue by subjecting mice deficient in each prostanoid receptor individually or mice treated with a subtype-specific antagonist to UV irradiation. Mice treated with an antagonist for prostaglandin E receptor subtype 4 (EP4), but not those deficient in other prostanoid receptors, show impaired UV-induced immunosuppression, whereas administration of an EP4 agonist rescues the impairment of the UV-induced immunosuppression in indomethacin-treated mice. The EP4 antagonist treatment suppresses an increase in the number of CD4+/forkhead box P3-positive (Foxp3+) regulatory T cells (Treg cells) in the peripheral lymph nodes (LNs) and dendritic cells expressing DEC205 in the LNs and the skin after UV irradiation. Furthermore, the EP4 antagonist treatment down-regulates UV-induced expression of receptor activator of NF-κB ligand (RANKL) in skin keratinocytes. Finally, administration of anti-RANKL antibody abolishes the restoration of UV-induced immunosuppression by EP4 agonism in indomethacin-treated mice. Thus, prostaglandin E2 (PGE2)-EP4 signaling mediates IN-induced immunosuppression by elevating the number of Treg cells through regulation of RANKL expression in the epidermis. [ABSTRACT FROM AUTHOR]

Idiopathic pulmonary fibrosis (IPF) is a progressive disease characterized by fibroblast proliferation and excess deposition of collagen and other extracellular matrix (ECM) proteins, which lead to distorted lung architecture and function. Given that anti-inflammatory or immunosuppressive therapy currently used for IPF does not improve disease progression therapies targeted to blocking the mechanisms of fibrogenesis are needed. Although transforming growth factor-β (TGF-β) functions are crucial in fibrosis, antagonizing this pathway in bleomycin-induced pulmonary fibrosis, an animal model of IPF, does not prevent fibrosis completely, indicating an additional pathway also has a key role in fibrogenesis. Given that the loss of cytosolic phospholipase A2 (cPLA2) suppresses bleomycin-induced pulmonary fibrosis, we examined the roles of prostaglandins using mice lacking each prostoaglandin receptor. Here we show that loss of prostaglandin F (PGF) receptor (FP) selectively attenuates pulmonary fibrosis while maintaining similar levels of alveolar inflammation and TGF-β stimulation as compared to wild-type (WT) mice, and that FP deficiency and inhibition of TGF-β signaling additively decrease fibrosis. Furthermore, PGF2α is abundant in bronchoalveolar lavage fluid (BALF) of subjects with IPF and stimulates proliferation and collagen production of lung fibroblasts via FP, independently of TGF-β. These findings show that PGF2α-FP signaling facilitates pulmonary fibrosis independently of TGF-β and suggests this signaling pathway as a therapeutic target for IPF. [ABSTRACT FROM AUTHOR]

Two distinct helper T (TH) subsets, TH1 and TH17, mediate tissue damage and inflammation in animal models of various immune diseases such as multiple sclerosis, rheumatoid arthritis, inflammatory bowel diseases and allergic skin disorders. These experimental findings, and the implication of these TH subsets in human diseases, suggest the need for pharmacological measures to manipulate these TH subsets. Here we show that prostaglandin E2 (PGE2) acting on its receptor EP4 on T cells and dendritic cells not only facilitates TH1 cell differentiation but also amplifies interleukin-23–mediated TH17 cell expansion in vitro. Administration of an EP4-selective antagonist in vivo decreases accumulation of both TH1 and TH17 cells in regional lymph nodes and suppresses the disease progression in mice subjected to experimental autoimmune encephalomyelitis or contact hypersensitivity. Thus, PGE2-EP4 signaling promotes immune inflammation through TH1 differentiation and TH17 expansion, and EP4 antagonism may be therapeutically useful for various immune diseases. [ABSTRACT FROM AUTHOR]

Physical interaction of T cells and dendritic cells (DCs) is essential for T cell proliferation and differentiation, but it has been unclear how this interaction is regulated physiologically. Here we show that DCs produce thromboxane A[SUB2] (TXA[SUB2]), whereas naive T cells express the thromboxane receptor (TP).In vitro, a TP agonist enhances random cell movement (chemokinesis) of naive but not memory T cells, impairs DC-T cell adhesion, and inhibits DC-dependent proliferation of T cells.In vivo, immune responses to foreign antigens are enhanced in TP-deficient mice, which also develop marked lymphadenopathy with age. Similar immune responses were seen in wild-type mice treated with a TP antagonist during the sensitization period. Thus, TXA[SUB2]-TP signaling modulates acquired immunity by negatively regulating DC-T cell interactions. [ABSTRACT FROM AUTHOR]

Antigen-specific immune responses in the skin are initiated by antigen uptake into Langerhans cells and the subsequent migration of these cells to draining lymph nodes. Although prostaglandin E[SUB2] (PGE[SUB2]) is produced substantially in skin exposed to antigen, its role remains unclear. Here we show that although Langerhans cells express all four PGE receptor subtypes, their migration to regional lymph nodes was decreased only in EP4-deficient (Ptger4[SUP-/-]) mice and in wild-type mice treated with an EP4 antagonist. An EP4 agonist promoted the migration of Langerhans cells, increased their expression of costimulatory molecules and enhanced their ability to stimulate T cells in the mixed lymphocyte reaction in vitro. Contact hypersensitivity to antigen was impaired in Ptger4[SUP-/-] mice and in wild-type mice treated with the EP4 antagonist during sensitization. PGE[SUB2]-EP4 signaling thus facilitates initiation of skin immune responses by promoting the migration and maturation of Langerhans cells. [ABSTRACT FROM AUTHOR]

Rac1 is a member of the Rho family of small GTPases that regulates cytoskeletal reorganization, membrane polarization, cell migration and proliferation. Recently, a self-activating mutation of Rac1, Rac1 P29S , has been identified as a recurrent somatic mutation frequently found in sun-exposed melanomas, which possesses increased inherent GDP/GTP exchange activity and cell transforming ability. However, the role of cellular Rac1-interacting proteins in the transforming potential of Rac1 P29S remains unclear. We found that the catalytic domain of DOCK1, a Rac-specific guanine nucleotide exchange factor (GEF) implicated in malignancy of a variety of cancers, can greatly accelerate the GDP/GTP exchange of Rac1 P29S . Enforced expression of Rac1 P29S induced matrix invasion and macropinocytosis in wild-type (WT) mouse embryonic fibroblasts (MEFs), but not in DOCK1-deficient MEFs. Consistently, a selective inhibitor of DOCK1 that blocks its GEF function suppressed the invasion and macropinocytosis in WT MEFs expressing Rac1 P29S . Human melanoma IGR-1 and breast cancer MDA-MB-157 cells harbor Rac1 P29S mutation and express DOCK1 endogenously. Genetic inactivation and pharmacological inhibition of DOCK1 suppressed their invasion and macropinocytosis. Taken together, these results indicate that DOCK1 is a critical regulator of the malignant phenotypes induced by Rac1 P29S , and suggest that targeting DOCK1 might be an effective approach to treat cancers associated with Rac1 P29S mutation., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Trafficking of immune cells is controlled by directed migration of relevant cells toward chemotactic signals. Actin cytoskeleton undergoes continuous remodeling and serves as machinery for cell migration. The mDia family of formins and the Wiskott-Aldrich syndrome protein (WASP)-Arp2/3 system are two major actin nucleating-polymerizing systems in mammalian cells, with the former producing long straight actin filaments and the latter producing branched actin meshwork. Although much is known about the latter, the physiological functions of mDia proteins are unclear. We generated mice deficient in one mDia isoform, mDia1. Although mDia1(-/-) mice were born and developed without apparent abnormality, mDia1(-/-) T lymphocytes exhibited impaired trafficking to secondary lymphoid organs in vivo and showed reduced chemotaxis, little actin filament formation, and impaired polarity in response to chemotactic stimuli in vitro. Similarly, mDia1(-/-) thymocytes showed reduced chemotaxis and impaired egression from the thymus. These results suggest that mDia1 plays a distinct role in chemotaxis in T lymphocyte trafficking.