International Journal of Colorectal Disease

, Volume 22, Issue 12, pp 1421–1427 | Cite as

The proinflammatory CXC-chemokines GRO-α/CXCL1 and MIG/CXCL9 are concomitantly expressed in ulcerative colitis and decrease during treatment with topical corticosteroids

  • Arne Egesten
  • Mette Eliasson
  • Anders I. Olin
  • Jonas S. Erjefält
  • Anders Bjartell
  • Per Sangfelt
  • Marie Carlson
Original Article

Abstract

Background

Ulcerative colitis is characterized by relapsing mucosal inflammation where the lesions include tissue-damaging granulocytes. In addition, T cells and natural killer (NK) cells play important pathophysiologic roles. Chemokines are a large family of peptides that play key roles in the regulation of inflammation. The CXC-chemokines, growth-related oncogene (GRO)-α/CXCL1 and interleukin (IL)-8/CXCL8, both recruit neutrophils and possess mitogenic properties, whereas the interferon-dependent CXC-chemokines monokine induced by gamma-interferon (MIG)/CXCL9, interferon-γ inducible protein of 10 kD/CXCL10, and IFN-inducible T cell alpha chemoattractant/CXCL11 recruit and activate T cells and NK cells.

Materials and methods

The expression of CXC-chemokines was studied in eight controls and in 11 patients suffering from ulcerative colitis in the distal part of the colon, before and during topical treatment with corticosteroids. Perfusates (obtained before, after 7 days, and after 28 days of treatment) and pinch biopsies (obtained before and after 28 days of treatment) were collected by colonoscopy. The rectal release of GRO-α and MIG was determined by enzyme-linked immunosorbent assay (ELISA), and tissue expression of the chemokines was detected in colonic tissue by immunohistochemistry.

Results

In perfusates, high levels of GRO-α, IL-8, and MIG were detected compared with controls (p = 0.02, 0.005, and p = 0.03, respectively). During treatment with corticosteroids, both GRO-α and MIG decreased. In clinical nonresponders, characterized by sustained inflammation, the levels of GRO-α and MIG remained elevated. Both epithelial cells and granulocytes, present in the submucosa, expressed GRO-α and MIG as detected by immunohistochemistry.

Conclusions

CXC-chemokines are likely to be important in the pathophysiology of ulcerative colitis and may become targets for novel treatment strategies. In addition, GRO-α may serve as a marker of disease activity.

Keywords

Ulcerative colitis GRO-α/CXCL1 MIG/CXCL9 Chemokines Corticosteroids 

Notes

Acknowledgments

We are grateful for statistical advice from Mikael Åström, technical assistance of Pia Andersson, and linguistic revision by Dr. Alan Chester. The study was supported by grants from The Bergh, Grönberg, Ihre, Julin, Kock, and Österlund foundations.

Competing interests

None declared.

References

  1. 1.
    Podolsky DK (2002) Inflammatory bowel disease. N Engl J Med 347:417–429CrossRefPubMedGoogle Scholar
  2. 2.
    Elliott SN, Wallace JL (1998) Neutrophil-mediated gastrointestinal injury. Can J Gastroenterol 12:559–568CrossRefPubMedGoogle Scholar
  3. 3.
    Egesten A, Andersson P, Persson T (2002) Eosinophils in gastrointestinal inflammation: from innocent bystanders to offenders. Scand J Gastroenterol 37:1117–1125CrossRefPubMedGoogle Scholar
  4. 4.
    Camoglio L, Te Velde AA, Tigges AJ, Das PK, Van Deventer SJ (1998) Altered expression of interferon-gamma and interleukin-4 in inflammatory bowel disease. Inflamm Bowel Dis 4:285–290PubMedGoogle Scholar
  5. 5.
    Fuss IJ, Heller F, Boirivant M, Leon F, Yoshida M, Fichtner-Feigl S, Yang Z, Exley M, Kitani A, Blumberg RS, Mannon P, Strober W (2004) Nonclassical CD1d-restricted NK T cells that produce IL-13 characterize an atypical Th2 response in ulcerative colitis. J Clin Invest 113:1490–1497CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Baggiolini M (2001) Chemokines in pathology and medicine. J Intern Med 250:91–104CrossRefPubMedGoogle Scholar
  7. 7.
    Luster AD (2001) Chemokines regulate lymphocyte homing to the intestinal mucosa. Gastroenterology 120:291–294CrossRefPubMedGoogle Scholar
  8. 8.
    Wen DZ, Rowland A, Derynck R (1989) Expression and secretion of gro/MGSA by stimulated human endothelial cells. EMBO J 8:1761–1766PubMedPubMedCentralGoogle Scholar
  9. 9.
    Sauty A, Dziejman M, Taha RA, Iarossi AS, Neote K, Garcia-Zepeda EA, Hamid Q, Luster AD (1999) The T cell-specific CXC chemokines IP-10, Mig, and I-TAC are expressed by activated human bronchial epithelial cells. J Immunol 162:3549–3558PubMedGoogle Scholar
  10. 10.
    Persson-Dajotoy T, Andersson P, Bjartell A, Calafat J, Egesten A (2003) Expression and production of the CXC chemokine growth-related oncogene-alpha by human eosinophils. J Immunol 170:5309–5316CrossRefPubMedGoogle Scholar
  11. 11.
    Jinquan T, Jing C, Jacobi HH, Reimert CM, Millner A, Quan S, Hansen JB, Dissing S, Malling HJ, Skov PS, Poulsen LK (2000) CXCR3 expression and activation of eosinophils: role of IFN-gamma-inducible protein-10 and monokine induced by IFN-gamma. J Immunol 165:1548–1556CrossRefPubMedGoogle Scholar
  12. 12.
    Addison CL, Daniel TO, Burdick MD, Liu H, Ehlert JE, Xue YY, Buechi L, Walz A, Richmond A, Strieter RM (2000) The CXC chemokine receptor 2, CXCR2, is the putative receptor for ELR+ CXC chemokine-induced angiogenic activity. J Immunol 165:5269–5277CrossRefPubMedGoogle Scholar
  13. 13.
    Romagnani P, Annunziato F, Lasagni L, Lazzeri E, Beltrame C, Francalanci M, Uguccioni M, Galli G, Cosmi L, Maurenzig L, Baggiolini M, Maggi E, Romagnani S, Serio M (2001) Cell cycle-dependent expression of CXC chemokine receptor 3 by endothelial cells mediates angiostatic activity. J Clin Invest 107:53–63CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Cole AM, Ganz T, Liese AM, Burdick MD, Liu L, Strieter RM (2001) IFN-inducible ELR CXC chemokines display defensin-like antimicrobial activity. J Immunol 167:623–627CrossRefPubMedGoogle Scholar
  15. 15.
    Ekbom A, Helmick C, Zack M, Adami HO (1990) Ulcerative colitis and colorectal cancer. A population-based study. N Engl J Med 323:1228–1233CrossRefPubMedGoogle Scholar
  16. 16.
    Sangfelt P, Carlson M, Thorn M, Lööf L, Raab Y (2001) Neutrophil and eosinophil granule proteins as markers of response to local prednisolone treatment in distal ulcerative colitis and proctitis. Am J Gastroenterol 96:1085–1090CrossRefPubMedGoogle Scholar
  17. 17.
    Binder V (1979) A comparison between clinical state, macroscopic and microscopic appearances of rectal mucosa, and cytologic picture of mucosal exudate in ulcerative colitis. Scand J Gastroenterol 5:627–632Google Scholar
  18. 18.
    Truelove SC, Richards WC (1956) Biopsy studies in ulcerative colitis. Br Med J 1:1315–13188CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Cordell JL, Falini B, Erber WN, Ghosh AK, Abdulaziz Z, MacDonald S, Pulford KA, Stein H, Mason DY (1984) Immunoenzymatic labeling of monoclonal antibodies using immune complexes of alkaline phosphatase and monoclonal anti-alkaline phosphatase (APAAP complexes). J Histochem Cytochem 32:219–229CrossRefPubMedGoogle Scholar
  20. 20.
    Sangfelt P, Carlson M, Thorn M, Xu S, Loof L, Raab Y (2002) Local release of human neutrophil lipocalin (HNL), IL-8, and TNF-alpha is decreased as response to topical prednisolone treatment in distal ulcerative colitis and proctitis. Dig Dis Sci 47:2064–2069CrossRefPubMedGoogle Scholar
  21. 21.
    Keshavarzian A, Fusunyan RD, Jacyno M, Winship D, MacDermott RP, Sanderson IR (1999) Increased interleukin-8 (IL-8) in rectal dialysate from patients with ulcerative colitis: evidence for a biological role for IL-8 in inflammation of the colon. Am J Gastroenterol 94:704–712CrossRefPubMedGoogle Scholar
  22. 22.
    Uguccioni M, Gionchetti P, Robbiani DF, Rizzello F, Peruzzo S, Campieri M, Baggiolini M (1999) Increased expression of IP-10, IL-8, MCP-1, and MCP-3 in ulcerative colitis. Am J Pathol 155:331–336CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Borregaard N, Cowland JB (1997) Granules of the human neutrophilic polymorphonuclear leukocyte. Blood 89:3503–3521PubMedGoogle Scholar
  24. 24.
    Egesten A, Eliasson M, Johansson HM, Olin AI, Mörgelin M, Mueller A, Pease JE, Frick IM, Björck L (2007) The CXC chemokine MIG/CXCL9 is important in innate immunity against Streptococcus pyogenes. J Infect Dis 195:684–693CrossRefPubMedGoogle Scholar
  25. 25.
    Lee J, Horuk R, Rice GC, Bennett GL, Camerato T, Wood WI (1992) Characterization of two high affinity human interleukin-8 receptors. J Biol Chem 267:16283–16287PubMedGoogle Scholar
  26. 26.
    Ahuja SK, Murphy PM (1996) The CXC chemokines growth-regulated oncogene (GRO) alpha, GRObeta, GROgamma, neutrophil-activating peptide-2, and epithelial cell-derived neutrophil-activating peptide-78 are potent agonists for the type B, but not the type A, human interleukin-8 receptor. J Biol Chem 271:20545–20550CrossRefPubMedGoogle Scholar
  27. 27.
    Loukinova E, Dong G, Enamorado-Ayalya I, Thomas GR, Chen Z, Schreiber H, Van Waes C (2000) Growth regulated oncogene-alpha expression by murine squamous cell carcinoma promotes tumor growth, metastasis, leukocyte infiltration and angiogenesis by a host CXC receptor-2 dependent mechanism. Oncogene 19:3477–3486CrossRefPubMedGoogle Scholar
  28. 28.
    Keane MP, Belperio JA, Xue YY, Burdick MD, Strieter RM (2004) Depletion of CXCR2 inhibits tumor growth and angiogenesis in a murine model of lung cancer. J Immunol 172:2853–2860CrossRefPubMedGoogle Scholar
  29. 29.
    Pan J, Burdick MD, Belperio JA, Xue YY, Gerard C, Sharma S, Dubinett SM, Strieter RM (2006) CXCR3/CXCR3 ligand biological axis impairs RENCA tumor growth by a mechanism of immunoangiostasis. J Immunol 176:1456–1464CrossRefPubMedGoogle Scholar
  30. 30.
    Lang KS, Georgiev P, Recher M, Navarini AA, Bergthaler A, Heikenwalder M, Harris NL, Junt T, Odermatt B, Clavien PA, Pircher H, Akira S, Hengartner H, Zinkernagel RM (2006) Immunoprivileged status of the liver is controlled by Toll-like receptor 3 signaling. J Clin Invest 116:2456–2463CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Podolin PL, Bolognese BJ, Foley JJ, Schmidt DB, Buckley PT, Widdowson KL, Jin Q, White JR, Lee JM, Goodman RB, Hagen TR, Kajikawa O, Marshall LA, Hay DW, Sarau HM (2002) A potent and selective nonpeptide antagonist of CXCR2 inhibits acute and chronic models of arthritis in the rabbit. J Immunol 169:6435–6444CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Arne Egesten
    • 1
  • Mette Eliasson
    • 1
  • Anders I. Olin
    • 1
  • Jonas S. Erjefält
    • 1
  • Anders Bjartell
    • 2
    • 4
  • Per Sangfelt
    • 3
  • Marie Carlson
    • 3
  1. 1.Department of Clinical Sciences LundLundSweden
  2. 2.Department of Clinical Sciences Malmö, Lund UniversityUniversity Hospital MalmöMalmöSweden
  3. 3.Department of Medical Sciences, Gastroenterology Research GroupUppsala UniversityUppsalaSweden
  4. 4.Department of UrologyMemorial Sloan-Kettering Cancer CenterNew YorkUSA

Personalised recommendations