| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
IL-17 Axis1
* Department of Physiology, Temple University School of Medicine, Philadelphia, PA 19140; and
Department of Biological Sciences, Rutgers University, Newark, NJ 07102
Although Crohn’s disease has been traditionally considered to be Th1-mediated, the newly identified Th17 cells emerged recently as crucial participants. Th1/Th17 differentiation is controlled primarily by the IL-12 family of cytokines secreted by activated dendritic cells (DCs) and macrophages. IL-23 and IL-12/IL-27 have opposite effects, supporting the Th17 and Th1 phenotypes, respectively. We found that PGE2, a major lipid mediator released in inflammatory conditions, shifts the IL-12/IL-23 balance in DCs in favor of IL-23, and propose that high levels of PGE2 exacerbate the inflammatory process in inflammatory bowel disease through the IL-23
IL-17 axis. We assessed the effects of PGE2 on IL-12, IL-27, and IL-23 and found that PGE2 promotes IL-23, inhibits IL-12 and IL-27 expression and release from stimulated DCs, and subsequently induces IL-17 production in activated T cells. The effects of PGE2 are mediated through the EP2/EP4 receptors on DCs. In vivo, we assessed the effects of PGE analogs in an experimental model for inflammatory bowel disease and found that the exacerbation of clinical symptoms and histopathology correlated with an increase in IL-23 and IL-17, a decrease in IL-12p35 expression in colon and mesenteric lymph nodes, and a substantial increase in the number of infiltrating neutrophils and of CD4+IL-17+ T cells in the colonic tissue. These studies suggest that high levels of PGE2 exacerbate the inflammatory process through the preferential expression and release of DC-derived IL-23 and the subsequent support of the autoreactive/inflammatory Th17 phenotype.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Institutes of Health/National Institute of Allergy and Infectious Diseases Grant RO1AI052306.
2 Address correspondence and reprint requests to Dr. Doina Ganea, Department of Physiology, Temple University School of Medicine, 3420 North Broad Street, Philadelphia, PA 19140. E-mail address: doina.ganea{at}temple.edu
3 Abbreviations used in this paper: IBD, inflammatory bowel disease; CrD, Crohn’s disease; UC, ulcerative colitis; TNBS, 2,4,6-trinitrobenzene sulfonic acid; DC, dendritic cell; rm, recombinant murine; MPO, myeloperoxidase; MLN, mesenteric lymph node; MPO, myeloperoxidase; LPDC, lamina propria DC; Cox, cyclooxygenase.
This article has been cited by other articles:
|
|
 |
|
  G. Murugaiyan and B. Saha Protumor vs Antitumor Functions of IL-17 J. Immunol., October 1, 2009; 183(7): 4169 - 4175. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Degagne, D. M. Grbic, A.-A. Dupuis, E. G. Lavoie, C. Langlois, N. Jain, G. A. Weisman, J. Sevigny, and F.-P. Gendron P2Y2 Receptor Transcription Is Increased by NF-{kappa}B and Stimulates Cyclooxygenase-2 Expression and PGE2 Released by Intestinal Epithelial Cells J. Immunol., October 1, 2009; 183(7): 4521 - 4529. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. T. Padol and R. H. Hunt Association of myocardial infarctions with COX-2 inhibition may be related to immunomodulation towards a Th1 response resulting in atheromatous plaque instability: an evidence-based interpretation Rheumatology, September 24, 2009; (2009) kep225v1. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Fortin, M. Raymond, V. Q. Van, M. Rubio, P. Gautier, M. Sarfati, and D. Franchimont A role for CD47 in the development of experimental colitis mediated by SIRP{alpha}+CD103- dendritic cells J. Exp. Med., August 31, 2009; 206(9): 1995 - 2011. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Kuwabara, F. Ishikawa, T. Yasuda, K. Aritomi, H. Nakano, Y. Tanaka, Y. Okada, M. Lipp, and T. Kakiuchi CCR 7 Ligands Are Required for Development of Experimental Autoimmune Encephalomyelitis through Generating IL-23-Dependent Th17 Cells J. Immunol., August 15, 2009; 183(4): 2513 - 2521. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. M. Aronoff, C. Lewis, C. H. Serezani, K. A. Eaton, D. Goel, J. C. Phipps, M. Peters-Golden, and P. Mancuso E-Prostanoid 3 Receptor Deletion Improves Pulmonary Host Defense and Protects Mice from Death in Severe Streptococcus pneumoniae Infection J. Immunol., August 15, 2009; 183(4): 2642 - 2649. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S Brand Crohn's disease: Th1, Th17 or both? The change of a paradigm: new immunological and genetic insights implicate Th17 cells in the pathogenesis of Crohn's disease Gut, August 1, 2009; 58(8): 1152 - 1167. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. Hu, F. Li, S. Mahavadi, and K. S. Murthy Upregulation of RGS4 expression by IL-1{beta} in colonic smooth muscle is enhanced by ERK1/2 and p38 MAPK and inhibited by the PI3K/Akt/GSK3{beta} pathway Am J Physiol Cell Physiol, June 1, 2009; 296(6): C1310 - C1320. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Nares, N. M. Moutsopoulos, N. Angelov, Z. G. Rangel, P. J. Munson, N. Sinha, and S. M. Wahl Rapid Myeloid Cell Transcriptional and Proteomic Responses to Periodontopathogenic Porphyromonas gingivalis Am. J. Pathol., April 1, 2009; 174(4): 1400 - 1414. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Boniface, K. S. Bak-Jensen, Y. Li, W. M. Blumenschein, M. J. McGeachy, T. K. McClanahan, B. S. McKenzie, R. A. Kastelein, D. J. Cua, and R. de Waal Malefyt Prostaglandin E2 regulates Th17 cell differentiation and function through cyclic AMP and EP2/EP4 receptor signaling J. Exp. Med., March 16, 2009; 206(3): 535 - 548. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Chizzolini, R. Chicheportiche, M. Alvarez, C. de Rham, P. Roux-Lombard, S. Ferrari-Lacraz, and J.-M. Dayer Prostaglandin E2 synergistically with interleukin-23 favors human Th17 expansion Blood, November 1, 2008; 112(9): 3696 - 3703. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S.L. Gaffen and G. Hajishengallis A New Inflammatory Cytokine on the Block: Re-thinking Periodontal Disease and the Th1/Th2 Paradigm in the Context of Th17 Cells and IL-17 Journal of Dental Research, September 1, 2008; 87(9): 817 - 828. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. J. E. Raveney, C. Richards, M.-L. Aknin, D. A. Copland, B. R. Burton, E. Kerr, L. B. Nicholson, N. A. Williams, and A. D. Dick The B Subunit of Escherichia coli Heat-Labile Enterotoxin Inhibits Th1 but Not Th17 Cell Responses in Established Experimental Autoimmune Uveoretinitis Invest. Ophthalmol. Vis. Sci., September 1, 2008; 49(9): 4008 - 4017. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Shiraishi, H. Yoshida, K. Saeki, Y. Miura, S. Watanabe, T. Ishizaki, M. Hashimoto, G. Takaesu, T. Kobayashi, and A. Yoshimura Prostaglandin E2 is a major soluble factor produced by stromal cells for preventing inflammatory cytokine production from dendritic cells Int. Immunol., September 1, 2008; 20(9): 1219 - 1229. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Khayrullina, J.-H. Yen, H. Jing, and D. Ganea In Vitro Differentiation of Dendritic Cells in the Presence of Prostaglandin E2 Alters the IL-12/IL-23 Balance and Promotes Differentiation of Th17 Cells J. Immunol., July 1, 2008; 181(1): 721 - 735. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. D. Woolard, L. L. Hensley, T. H. Kawula, and J. A. Frelinger Respiratory Francisella tularensis Live Vaccine Strain Infection Induces Th17 Cells and Prostaglandin E2, Which Inhibits Generation of Gamma Interferon-Positive T Cells Infect. Immun., June 1, 2008; 76(6): 2651 - 2659. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
