Interferon-gamma limits Th1 lymphocyte adhesion to inflamed endothelium: a nitric oxide regulatory feedback mechanism.
CD4(+) T helper (Th1 and Th2) cell localization to a site of inflammation is important for the development, maintenance and regulation of an immune response. The factors that regulate Th1 and Th2 cell recruitment into tissue are not fully understood. The aim of the present study was to examine the effect of different cytokine microenvironments on the recruitment of Th1 and Th2 lymphocytes into tissue. Fluorescently labelled Th1 or Th2 lymphocyte-endothelial interactions were observed via intravital microscopy of the cytokine-treated cremaster muscle. Our results show that TNF-alpha alone is sufficient to maximally recruit Th1 cells. Surprisingly, treatment with TNF-alpha + IFN-gamma significantly decreased Th1 adhesion and emigration in comparison to TNF-alpha treatment alone. The decreased adhesion of Th1 cells in response to TNF-alpha + IFN-gamma reflected a decreased ability to bind to ICAM-1 and was iNOS-dependent. This phenomenon was not observed with Th2 cells. These results suggest that IFN-gamma may play a key immunomodulatory role in the recruitment of different T lymphocyte subsets. Indeed, blockade of IFN-gamma or iNOS function during the Th1-mediated contact hypersensitivity response resulted in an acceleration and exacerbation of the late-phase inflammatory response.
Norman
M Ursula
MU
Immunology Research Group, Department of Physiology and Biophysics, Faculty of Medicine, University of Calgary, Calgary, AB, Canada.
Zbytnuik
Lori
L
Kubes
Paul
P
D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects / Q000276:immunology; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology; D004730:Endothelium, Vascular / Q000166:cytology* / Q000187:drug effects / Q000276:immunology; D025461:Feedback, Physiological / Q000276:immunology; D007249:Inflammation / Q000276:immunology / Q000473:pathology; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology / Q000502:physiology*; D036904:Leukocyte Rolling / Q000187:drug effects; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009132:Muscles / Q000098:blood supply; D009504:Neutrophils / Q000166:cytology; D009569:Nitric Oxide / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000235:genetics; D017471:Receptors, Interferon / Q000235:genetics; D012039:Regional Blood Flow / Q000187:drug effects; D012867:Skin / Q000098:blood supply / Q000276:immunology / Q000473:pathology; D018417:Th1 Cells / Q000166:cytology* / Q000378:metabolism / Q000637:transplantation; D018418:Th2 Cells / Q000166:cytology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D000096743:Interferon gamma Receptor
D018799:Intercellular Adhesion Molecule-1; D007371:Interferon-gamma; D016169:Lymphocyte Function-Associated Antigen-1; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D017471:Receptors, Interferon; D014409:Tumor Necrosis Factor-alpha; D000096743:Interferon gamma Receptor; C090509:Icam1 protein, mouse; C496317:Nos2 protein, mouse