International Immunology Advance Access originally published online on November 28, 2007
International Immunology 2008 20(1):141-154; doi:10.1093/intimm/dxm126
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Massive but selective cytokine dysregulation in the colon of IL-10–/– mice revealed by multiplex analysis
1 Department of Diagnostic Sciences, Dental Branch, University of Texas Health Science Center at Houston, 6516 MD Anderson Boulevard, Houston, TX, USA
2 Department of Pathology, Baylor College of Medicine, Houston, TX, USA
Correspondence to: J. R. Klein; E-mail: john.r.klein{at}uth.tmc.edu
IL-10-deficient mice develop enterocolitis due to a failure of cytokine regulation; however, the full scope of that response remains poorly defined. Using multiplex analysis to quantify the activity of 23 regulatory and effector cytokines produced by colonic leukocytes, we demonstrate a vast dysregulation process of 18 cytokines in IL-10–/– mice from 7 to 27 weeks of age. Of those, IL-12p40, IL-6, granulocyte macrophage colony-stimulating factor, IFN-
, IL-13 and monocyte chemoattractant protein-1 (MCP-1) had the highest single correlations with pathology (r = 0.7766–0.7016). Importantly, there were strong associations (r = 0.7071–0.9074) between those cytokines and as many as 10 additional cytokines, indicating a high degree of cytokine complexity as disease progressed. IL-17 was notable in that it was produced at high levels by colonic leukocytes from IL-10–/– mice with pathology ranging from mild to severe, though it was not produced by healthy IL-10–/– mice lacking pathology. Tumor necrosis factor 
(TNF) by itself displayed only a modest association with pathology (r = 0.6340), ranking sixth lowest, though it cross-correlated strongly with the synthesis of 12 other cytokines, implying that the destructive effects associated with TNF may be due to interactions of multiple cytokine activities. IL-23 expression did not correlate with pathology, possibly suggesting that IL-23 is involved in the initiation but not the perpetuation of inflammation. Four cytokines (IL-2, IL-3, IL-4 and IL-5) remained negative in IL-10–/– mice, demonstrating that cytokine dysregulation was not universal. These findings emphasize the need to better understand cytokine networks in chronic inflammation and they provide a rationale for combining immunotherapies in the treatment of intestinal inflammation.
Keywords: cell activation, chemokine, cytokine, mucosa, rodent
Transmitting editor: C. Terhorst
Received 12 May 2007, accepted 25 October 2007.
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