The Proinflammatory Effect of Prostaglandin E2 in Experimental Inflammatory Bowel Disease Is Mediated through the IL-23→IL-17 Axis

Sheibanie, Amir F.; Yen, Jui‐Hung; Khayrullina, Tanzilya; Emig, Frances A.; Zhang, Ming; Tuma, Ronald F.; Ganea, Doina

doi:10.4049/jimmunol.178.12.8138

Cited by 248 publications

(206 citation statements)

References 71 publications

(68 reference statements)

Supporting

Mentioning

189

Contrasting

Unclassified

Order By: Relevance

“…Therefore, these EPs are candidates for the downstream effectors of PGE 2 . Indeed, the exogenous and endogenous PGE 2 activates EP2 and EP4 on antigen presenting cells to stimulate expression of IL-23 and IL-6, resulting in a shift toward T H 17 responses (27)(28)(29)(30). PGE 2 synergized with IL-23 in expanding human T H 17 cell (31) and directly promoted differentiation of human and murine T H 17 cells through …”

Section: Discussionmentioning

confidence: 99%

Targeted lipidomics reveals mPGES-1-PGE2 as a therapeutic target for multiple sclerosis

Kihara

Matsushita

Kita

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

123

104

View full text Add to dashboard Cite

The arachidonic acid (AA) cascade produces eicosanoids, such as prostaglandins (PGs), that regulate physiological and pathological functions. Although various nonsteroidal anti-inflammatory drugs have been developed, blocking upstream components (cyclooxygenase-1 and -2) of the AA cascade leads to severe side effects, including gastrointestinal ulcers and cardiovascular events, respectively, due to the complexity of the AA cascade. Here, using an AA cascade-targeted lipidomics approach, we report that microsomal PGE synthase 1 (mPGES-1) plays a key role in experimental autoimmune encephalomyelitis (EAE). Eicosanoids (mainly PGD 2) are produced constitutively in the spinal cord of naive mice. However, in EAE lesions, the PGE 2 pathway is favored and the PGD2, PGI2, and 5-lipoxygenase pathways are attenuated. Furthermore, mPGES-1 ؊/؊ mice showed less severe symptoms of EAE and lower production of IL-17 and IFN-␥ than mPGES-1 ؉/؉ mice. Expression of PGE2 receptors (EP1, EP2, and EP4) was elevated in EAE lesions and correlated with clinical symptoms. Immunohistochemistry on central nervous systems of EAE mice and multiple sclerosis (MS) patients revealed overt expression of mPGES-1 protein in microglia/macrophages. Thus, the mPGES-1-PGE 2-EPs axis of the AA cascade may exacerbate EAE pathology. Our findings have important implications for the design of therapies for MS.autoimmunity ͉ demyelination ͉ lipid mediator ͉ mass spectrometry ͉ Th17

show abstract

Section: Discussionmentioning

confidence: 99%

Targeted lipidomics reveals mPGES-1-PGE2 as a therapeutic target for multiple sclerosis

Kihara

Matsushita

Kita

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

123

104

View full text Add to dashboard Cite

show abstract

“…In agreement with our results, previous reports also described the induction of Th17 profiles through the release of IL-23 by inflammatory DCs. 64,65 That DCs are inflammatory as derived from bone marrow precursors 26 is probably critical for the induction of CD4 + cells producing IL-17 against lipid mediators such as prostaglandin E 2 and LTC 4 . It is known that Th17 cells mediate protection against extracellular pathogens via neutrophil recruitment, 66 but also play a central role in immunopathology.…”

Section: Discussionmentioning

confidence: 99%

Leukotriene C4 prevents the complete maturation of murine dendritic cells and modifies interleukin-12/interleukin-23 balance

Álvarez¹,

Amaral²,

Langellotti³

et al. 2011

Immunology

View full text Add to dashboard Cite

Summary Leukotriene C4 is an important mediator in the development of inflammatory reactions and ischaemia. Previous studies have shown that leukotriene C4 is able to modulate the function of dendritic cells (DCs) and induce their chemotaxis from skin to lymph node. In this study, we decided to evaluate the modulation exerted by leukotriene C4 on DCs, depending on their status of activation. We showed for the first time that leukotriene C4 stimulates endocytosis both in immature and lipopolysaccharide (LPS) ‐activated DCs. Moreover, it suppressed the interleukin‐12p70 (IL‐12p70) release, but induces the secretion of IL‐23 by DCs activated with LPS and promotes the expansion of T helper type 17 (Th17) lymphocytes. Furthermore, blocking the release of IL‐23 reduced the percentages of CD4+ T cells producing IL‐17 in a mixed lymphocyte reaction. Ours results suggest that leukotriene C4 interferes with the complete maturation of inflammatory DCs in terms of phenotype and antigen uptake, while favouring the release of IL‐23, the main cytokine involved in the maintenance of the Th17 profile.

show abstract

“…In recent studies, several reagents, including whole pathogens, have been found to stimulate DCs to produce IL-23 (30). Serum amyloid A, an acute phase protein, PGE 2 , and phagocytosis of apoptotic neutrophils, each of which are found in inflammatory conditions, have been shown to generate IL-23 production by DCs (31)(32)(33)(34). These stimulators might enhance the constitutive production of CCL19 by DCs, which results in augmentation of IL-23 production in an autocrine manner.…”

Section: Figurementioning

confidence: 99%

CCR 7 Ligands Are Required for Development of Experimental Autoimmune Encephalomyelitis through Generating IL-23-Dependent Th17 Cells

Kuwabara¹,

Ishikawa²,

Yasuda³

et al. 2009

The Journal of Immunology

View full text Add to dashboard Cite

CCL19 and CCL21 are thought to be critical for experimental autoimmune encephalomyelitis (EAE) induction, but their precise role is unknown. We examined the role of these chemokines in inducing EAE. C57BL/6 mice lacking expression of these chemokines (plt/plt mice) or their receptor CCR7 were resistant to EAE induced with myelin oligodendrocyte glycoprotein peptide 35–55 (MOG35–55) and pertussis toxin. However, passive transfer of pathogenic T cells from wild-type mice induced EAE in plt/plt mice, suggesting a defect independent of the role of CCR7 ligands in the migration of immune cells. Examination of draining lymph node (DLN) cells from MOG35–55-immunized plt/plt mice found decreased IL-23 and IL-12 production by plt/plt dendritic cells (DCs) and a concomitant defect in Th17 cell and Th1 cell generation. In contrast, production of the Th17 lineage commitment factors IL-6 and TGF-β were unaffected by loss of CCR7 ligands. The adoptive transfer of in vitro-generated Th17 cells from DLN cells of MOG35–55-immunized plt/plt mice developed EAE in wild-type recipient mice, whereas that of Th1 cells did not. Pathogenic Th17 cell generation was restored in plt/plt DLNs with the addition of exogenous IL-23 or CCL19/CCL21 and could be reversed by inclusion of anti-IL-23 mAb in cultures. Exogenous CCL19/CCL21 induced IL-23p19 expression and IL-23 production by plt/plt or wild-type DCs. Therefore, CCR7 ligands have a novel function in stimulating DCs to produce IL-23 and are important in the IL-23-dependent generation of pathogenic Th17 cells in EAE induction.

show abstract

The Proinflammatory Effect of Prostaglandin E2 in Experimental Inflammatory Bowel Disease Is Mediated through the IL-23→IL-17 Axis

Cited by 248 publications

References 71 publications

Targeted lipidomics reveals mPGES-1-PGE2 as a therapeutic target for multiple sclerosis

Targeted lipidomics reveals mPGES-1-PGE2 as a therapeutic target for multiple sclerosis

Leukotriene C4 prevents the complete maturation of murine dendritic cells and modifies interleukin-12/interleukin-23 balance

CCR 7 Ligands Are Required for Development of Experimental Autoimmune Encephalomyelitis through Generating IL-23-Dependent Th17 Cells

Contact Info

Product

Resources

About