Massive but selective cytokine dysregulation in the colon of IL-10-/- mice revealed by multiplex analysis.
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-gamma, 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 alpha (TNFalpha) 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 TNFalpha 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.
Department of Diagnostic Sciences, Dental Branch, University of Texas Health Science Center at Houston, 6516 MD Anderson Boulevard, Houston, TX, USA.
Dina
D
Montufar-Solis
Jeremy
J
Schaefer
M John
MJ
Hicks
John R
JR
Klein
D000818:Animals; D003092:Colitis / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology*; D003106:Colon / Q000166:cytology / Q000276:immunology / Q000473:pathology*; D016207:Cytokines / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D004847:Epithelial Cells / Q000166:cytology / Q000276:immunology / Q000473:pathology*; D005260:Female; D016753:Interleukin-10 / Q000172:deficiency* / Q000235:genetics; D007962:Leukocytes / Q000166:cytology / Q000276:immunology / Q000473:pathology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C
D016207:Cytokines; D016753:Interleukin-10