Abstract
Background
Hypoadiponectinemia has been associated with states of chronic inflammation in humans. Mesenteric fat hypertrophy and low adiponectin have been described in patients with Crohn’s disease. We investigated whether adiponectin and the plant-derived homolog, osmotin, are beneficial in a murine model of colitis.
Methods
C57BL/6 mice were injected (i.v.) with an adenoviral construct encoding the full-length murine adiponectin gene (AN+DSS) or a reporter—LacZ (Ctr and V+DSS groups) prior to DSS colitis protocol. In another experiment, mice with DSS colitis received either osmotin (Osm+DSS) or saline (DSS) via osmotic pumps. Disease progression and severity were evaluated using body weight, stool consistency, rectal bleeding, colon lengths, and histology. In vitro experiments were carried out in bone marrow-derived dendritic cells.
Results
Mice overexpressing adiponectin had lower expression of proinflammatory cytokines (TNF, IL-1β), adipokines (angiotensin, osteopontin), and cellular stress and apoptosis markers. These mice had higher levels of IL-10, alternative macrophage marker, arginase 1, and leukoprotease inhibitor. The plant adiponectin homolog osmotin similarly improved colitis outcome and induced robust IL-10 secretion. LPS induced a state of adiponectin resistance in dendritic cells that was reversed by treatment with PPARγ agonist and retinoic acid.
Conclusion
Adiponectin exerted protective effects during murine DSS colitis. It had a broad activity that encompassed cytokines, chemotactic factors as well as processes that assure cell viability during stressful conditions. Reducing adiponectin resistance or using plant-derived adiponectin homologs may become therapeutic options in inflammatory bowel disease.
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Abbreviations
- Ao:
-
Angiotensinogen
- ACE:
-
Angiotensin converting enzyme
- AN:
-
Adiponectin
- AT1a:
-
Angiotensin receptor 1a
- BIP:
-
Endoplasmic reticulum-binding protein (Hsp70)
- CASP12:
-
Caspase 12
- CCR2:
-
Chemokine (C–C motif), receptor2
- CD14:
-
Cluster of differentiation 14
- CHOP:
-
C/EBP homologous protein
- COX2 :
-
Cyclooxygenase 2
- DC:
-
Dendritic cells
- DSS:
-
Dextran sodium sulfate
- ER:
-
Endoplasmic reticulum
- IBD:
-
Inflammatory bowel disease
- IL10:
-
Interleukin 10
- LPS:
-
Lipopolysaccharide
- MCP1:
-
Monocyte chemotactic protein-1
- NOD2:
-
Nucleotide-binding oligomerization domain containing 2
- PCNA:
-
Proliferating cell nuclear antigen
- PGE2:
-
prostaglandin E2
- PPARΎ :
-
Peroxisome proliferator-activated receptor γ
- P38MAPK:
-
p38 mitogen-activated protein kinase
- SLPi:
-
Secretory leukoprotease inhibitor
- Th1, 2:
-
T helper cell type 1, 2
- TLR:
-
Toll-like receptor
- TNFα:
-
Tumor necrosis factor α
References
Marks DJ, Segal AW. Innate immunity in inflammatory bowel disease: a disease hypothesis. J Pathol. 2008;214:260–266.
Crohn BBGL, Oppenheimer GD. Regional ileitis, a pathological and clinical entity. J Am Med Assoc. 1932;99:1323–1329.
Desreumaux P, Ernst O, Geboes K, et al. Inflammatory alterations in mesenteric adipose tissue in Crohn’s disease. Gastroenterology. 1999;117:73–81.
Sheehan AL, Warren BF, Gear MW, et al. Fat-wrapping in Crohn’s disease: pathological basis and relevance to surgical practice. Br J Surg. 1992;79:955–958.
Smedh K, Olaison G, Nystrom PO, et al. Intraoperative enteroscopy in Crohn’s disease. Br J Surg. 1993;80:897–900.
Borley NR, Mortensen NJ, Jewell DP, et al. The relationship between inflammatory and serosal connective tissue changes in ileal Crohn’s disease: evidence for a possible causative link. J Pathol. 2000;190:196–202.
Ajuwon KM, Banz W, Winters TA. Stimulation with peptidoglycan induces interleukin 6 and TLR2 expression and a concomitant downregulation of expression of adiponectin receptors 1 and 2 in 3T3-L1 adipocytes. J Inflamm [Lond]. 2009;6:8.
Yoshitaka U, Hiroshi Y, Hiroshi T, et al. Adiponectin deficiency is associated with severe polymicrobial sepsis, high inflammatory cytokine levels, and high mortality. Surgery. 2009;145:550–557.
Ran J, Hirano T, Fukui T, et al. Angiotensin II infusion decreases plasma adiponectin level via its type 1 receptor in rats: an implication for hypertension-related insulin resistance. Metabolism. 2006;55:478–488.
Haxhija EQ, Yang H, Spencer AU, et al. Modulation of mouse intestinal epithelial cell turnover in the absence of angiotensin converting enzyme. Am J Physiol Gastrointest Liver Physiol. 2008;295:G88–G98.
Shen XZ, Xiao HD, Li P, et al. Tissue specific expression of angiotensin converting enzyme: a new way to study an old friend. Int Immunopharmacol. 2008;8:171–176.
Santiago OI, Rivera E, Ferder L, et al. An angiotensin II receptor antagonist reduces inflammatory parameters in two models of colitis. Regul Pept. 2008;146:250–259.
Chinetti G, Zawadski C, Fruchart JC, et al. Expression of adiponectin receptors in human macrophages and regulation by agonists of the nuclear receptors PPARalpha, PPARgamma, and LXR. Biochem Biophys Res Commun. 2004;314:151–158.
Ramakers JD, Verstege MI, Thuijls G, et al. The PPARgamma agonist rosiglitazone impairs colonic inflammation in mice with experimental colitis. J Clin Immunol. 2007;27:275–283.
Martinet W, De Meyer GRY. Autophagy in atherosclerosis: a cell survival and death phenomenon with therapeutic potential. Circ Res. 2009;104:304–317.
Kuballa P, Huett A, Rioux JD, et al. Impaired autophagy of an intracellular pathogen induced by a Crohn’s disease associated ATG16L1 variant. PLoS ONE. 2008;3:e3391.
Hampe J, Franke A, Rosenstiel P, et al. A genome-wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn disease in ATG16L1. Nat Genet. 2007;39:207–211.
He ZQ, Zhen Y, Liang C, et al. Vicious cycle composed of gut flora and visceral fat: a novel explanation of the initiation and progression of atherosclerosis. Med Hypotheses. 2008;70:808–811.
Cooper HS, Murthy SN, Shah RS, et al. Clinicopathologic study of dextran sulfate sodium experimental murine colitis. Lab Invest. 1993;69:238–249.
Khan WI, Motomura Y, Wang H, et al. Critical role of MCP-1 in the pathogenesis of experimental colitis in the context of immune and enterochromaffin cells. Am J Physiol Gastrointest Liver Physiol. 2006;291:G803–G811.
Sasaki M, Mathis JM, Jennings MH, et al. Reversal of experimental colitis disease activity in mice following administration of an adenoviral IL-10 vector. J Inflamm [Lond]. 2005;2:13.
Ni J, Chen SF, Hollander D. Effects of dextran sulphate sodium on intestinal epithelial cells and intestinal lymphocytes. Gut. 1996;39:234–241.
Renes IB, Verburg M, Van Nispen DJ, et al. Epithelial proliferation, cell death, and gene expression in experimental colitis: alterations in carbonic anhydrase I, mucin MUC2, and trefoil factor 3 expression. Int J Colorectal Dis. 2002;17:317–326.
Bergenfeldt M, Nystrom M, Bohe M, et al. Localization of immunoreactive secretory leukocyte protease inhibitor [SLPI] in intestinal mucosa. J Gastroenterol. 1996;31:18–23.
Yang J, Zhu J, Sun D, et al. Suppression of macrophage responses to bacterial lipopolysaccharide [LPS] by secretory leukocyte protease inhibitor [SLPI] is independent of its anti-protease function. Biochim Biophys Acta. 2005;1745:310–317.
Benigni A, Cassis P, Remuzzi G. Angiotensin II revisited: new roles in inflammation, immunology and aging. EMBO Mol Med. 2010;2:247–257.
Agnholt J, Kelsen J, Schack L, et al. Osteopontin, a protein with cytokine-like properties, is associated with inflammation in Crohn’s disease. Scand J Immunol. 2007;65:453–460.
Zhong J, Eckhardt ER, Oz HS, et al. Osteopontin deficiency protects mice from dextran sodium sulfate-induced colitis. Inflamm Bowel Dis. 2006;12:790–796.
Moriuchi A, Yamasaki H, Shimamura M, et al. Induction of human adiponectin gene transcription by telmisartan, angiotensin receptor blocker, independently on PPAR-gamma activation. Biochem Biophys Res Commun. 2007;356:1024–1030.
Sanchez-Lemus E, Benicky J, Pavel J, et al. Angiotensin II AT1 blockade reduces the lipopolysaccharide-induced innate immune response in rat spleen. Am J Physiol Regul Integr Comp Physiol. 2009;296:R1376–R1384.
Kaser A, Lee AH, Franke A, et al. XBP1 links ER stress to intestinal inflammation and confers genetic risk for human inflammatory bowel disease. Cell. 2008;134:743–756.
McGuckin MA, Eri RD, Das I, et al. ER stress and the unfolded protein response in intestinal inflammation. Am J Physiol Gastrointest Liver Physiol. 2010;298:G820–G832.
Fukata M, Chen A, Klepper A, et al. Cox-2 is regulated by Toll-like receptor-4 [TLR4] signaling: Role in proliferation and apoptosis in the intestine. Gastroenterology. 2006;131:862–877.
Ibeas JI, Yun DJ, Damsz B, et al. Resistance to the plant PR-5 protein osmotin in the model fungus Saccharomyces cerevisiae is mediated by the regulatory effects of SSD1 on cell wall composition. Plant J. 2001;25:271–280.
Narasimhan ML, Coca MA, Jin J, et al. Osmotin is a homolog of mammalian adiponectin and controls apoptosis in yeast through a homolog of mammalian adiponectin receptor. Mol Cell. 2005;17:171–180.
Berndt BE, Zhang M, Chen GH, et al. The role of dendritic cells in the development of acute dextran sulfate sodium colitis. J Immunol. 2007;179:6255–6262.
Appel S, Mirakaj V, Bringmann A, et al. PPAR-gamma agonists inhibit toll-like receptor-mediated activation of dendritic cells via the MAP kinase and NF-kappaB pathways. Blood. 2005;106:3888–3894.
Iliev ID, Mileti E, Matteoli G, et al. Intestinal epithelial cells promote colitis-protective regulatory T-cell differentiation through dendritic cell conditioning. Mucosal Immunol. 2009;2:340–350.
Wolf AM, Wolf D, Rumpold H, et al. Adiponectin induces the anti-inflammatory cytokines IL-10 and IL-1RA in human leukocytes. Biochem Biophys Res Commun. 2004;323:630–635.
Wiecek A, Adamczak M, Chudek J. Adiponectin-an adipokine with unique metabolic properties. Nephrol Dial Transplant. 2007;22:981–988.
Nishihara T, Matsuda M, Araki H, et al. Effect of adiponectin on murine colitis induced by dextran sulfate sodium. Gastroenterology. 2006;131:853–861.
Pini M, Gove ME, Fayad R, et al. Adiponectin deficiency does not affect development and progression of spontaneous colitis in IL-10 knockout mice. Am J Physiol Gastrointest Liver Physiol. 2009;296:G382–G387.
Park P-h, Huang H, McMullen MR, et al. Activation of cyclic-AMP response element binding protein contributes to adiponectin-stimulated interleukin-10 expression in raw 264.7 macrophages. J Leukoc Biol. 2008;83:1258–1266.
Fayad R, Pini M, Sennello JA, et al. Adiponectin deficiency protects mice from chemically induced colonic inflammation. Gastroenterology. 2007;132:601–614.
Huang H, Park PH, McMullen MR, et al. Mechanisms for the anti-inflammatory effects of adiponectin in macrophages. J Gastroenterol Hepatol. 2008;23:S50–S53.
Thakur V, Pritchard MT, McMullen MR, et al. Adiponectin normalizes LPS-stimulated TNF-alpha production by rat Kupffer cells after chronic ethanol feeding. Am J Physiol Gastrointest Liver Physiol. 2006;290:G998–G1007.
Wolf AM, Wolf D, Rumpold H, et al. Adiponectin induces the anti-inflammatory cytokines IL-10 and IL-1RA in human leukocytes. Biochem Biophys Res Commun. 2004;323:630–635.
Ho VW, Sly LM. Derivation and characterization of murine alternatively activated [M2] macrophages. Methods Mol Biol. 2009;531:173–185.
Lumeng CN, Bodzin JL, Saltiel AR. Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J Clin Invest. 2007;117:175–184.
Sag D, Carling D, Stout RD, et al. Adenosine 5′-monophosphate-activated protein kinase promotes macrophage polarization to an anti-inflammatory functional phenotype. J Immunol. 2008;181:8633–8641.
Lovren F, Pan Y, Quan A, et al. Adiponectin primes human monocytes into alternative anti-inflammatory M2 macrophages. Am J Physiol Heart Circ Physiol. 2010.
Ajuebor MN, Swain MG. Role of chemokines and chemokine receptors in the gastrointestinal tract. Immunology. 2002;105:137–143.
Andres PG, Beck PL, Mizoguchi E, et al. Mice with a selective deletion of the CC chemokine receptors 5 or 2 are protected from dextran sodium sulfate-mediated colitis: lack of CC chemokine receptor 5 expression results in a NK1.1+ lymphocyte-associated Th2-type immune response in the intestine. J Immunol. 2000;164:6303–6312.
Doumas S, Kolokotronis A, Stefanopoulos P. Anti-inflammatory and antimicrobial roles of secretory leukocyte protease inhibitor. Infect Immun. 2005;73:1271–1274.
Hattori Y, Nakano Y, Hattori S, et al. High molecular weight adiponectin activates AMPK and suppresses cytokine-induced NF-kappaB activation in vascular endothelial cells. FEBS Lett. 2008;582:1719–1724.
Tomizawa A, Hattori Y, Kasai K, et al. Adiponectin induces NF-kappaB activation that leads to suppression of cytokine-induced NF-kappaB activation in vascular endothelial cells: globular adiponectin vs. high molecular weight adiponectin. Diab Vasc Dis Res. 2008;5:123–127.
Schmid M, Fellermann K, Fritz P, et al. Attenuated induction of epithelial and leukocyte serine antiproteases elafin and secretory leukocyte protease inhibitor in Crohn’s disease. J Leukoc Biol. 2007;81:907–915.
Grossmann ME, Mizuno NK, Bonorden MJ, et al. Role of the adiponectin leptin ratio in prostate cancer. Oncol Res. 2009;18:269–277.
Varol C, Landsman L, Fogg DK, et al. Monocytes give rise to mucosal, but not splenic, conventional dendritic cells. J Exp Med. 2007;204:171–180.
Thompson PW, Bayliffe AI, Warren AP, et al. Interleukin-10 is upregulated by nanomolar rosiglitazone treatment of mature dendritic cells and human CD4+ T cells. Cytokine. 2007;39:184–191.
Lewis JD, Lichtenstein GR, Stein RB, et al. An open-label trial of the PPAR-gamma ligand rosiglitazone for active ulcerative colitis. Am J Gastroenterol. 2001;96:3323–3328.
Brandl K, Rutschmann S, Li X, et al. Enhanced sensitivity to DSS colitis caused by a hypomorphic Mbtps1 mutation disrupting the ATF6-driven unfolded protein response. Proc Natl Acad Sci USA. 2009;106:3300–3305.
Anna S, Pedro AR, Hannelore D, et al. Interleukin-10 blocked endoplasmic reticulum stress in intestinal epithelial cells: impact on chronic inflammation. Gastroenterology. 2007;132:190–207.
Park PH, Huang H, McMullen MR, et al. Activation of cyclic-AMP response element binding protein contributes to adiponectin-stimulated interleukin-10 expression in RAW 264.7 macrophages. J Leukoc Biol. 2008;83:1258–1266.
Kadowaki T, Yamauchi T, Kubota N, et al. Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome. J Clin Invest. 2006;116:1784–1792.
Szegezdi E, Fitzgerald U, Samali A. Caspase-12 and ER-stress-mediated apoptosis: the story so far. Ann N Y Acad Sci. 2003;1010:186–194.
Zheng L, Riehl TE, Stenson WF. Regulation of colonic epithelial repair in mice by Toll-like receptors and hyaluronic acid. Gastroenterology. 2009;137:2041–2051.
Morteau O, Morham SG, Sellon R, et al. Impaired mucosal defense to acute colonic injury in mice lacking cyclooxygenase-1 or cyclooxygenase-2. J Clin Invest. 2009;105:469–478.
Acknowledgments
This work was supported by grants from Broad Medical Foundation, UCB Inc., Kentucky Science & Engineering Foundation (RA), and from NIH-DK07778-07 (VA). There are no competing financial interests to declare.
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Arsenescu, V., Narasimhan, M.L., Halide, T. et al. Adiponectin and Plant-Derived Mammalian Adiponectin Homolog Exert a Protective Effect in Murine Colitis. Dig Dis Sci 56, 2818–2832 (2011). https://doi.org/10.1007/s10620-011-1692-0
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DOI: https://doi.org/10.1007/s10620-011-1692-0