A soluble factor produced by lamina propria mononuclear cells is required for TNF-alpha enhancement of IFN-gamma production by T cells.
The role of TNF-alpha in the mucosal inflammation of Crohn's disease has been demonstrated by the prolonged clinical responses and/or remissions among patients receiving i.v. infusion of anti-TNF-alpha. A correlation between TNF-alpha and elevated IFN-gamma production is suggested by the reduction in the number of IFN-gamma producing lamina propria mononuclear cells (LPMC) found in colonic biopsies from anti-TNF-alpha-treated patients. The aim of this study was to define the mechanism of TNF-alpha-augmented mucosal T cell IFN-gamma production. In this paper we present evidence that cultured LPMC secrete a factor which acts on preactivated T cells in concert with TNF-alpha to augment IFN-gamma production. This activity is independent of IL-12 and IL-18, the well-documented potentiators of IFN-gamma expression, and is not produced by PBMC. Peripheral blood PHA-activated T cells incubated in supernatants from LPMC became responsive to TNF-alpha by increasing IFN-gamma output upon stimulation. These results are consistent with a model in which LPMC, but not PBMC, release an unidentified substance when cultured in vitro with low dose IL-2. This substance can act on preactivated peripheral T cells, as well as on lamina propria T cells, conditioning them to respond to TNF-alpha by increased IFN-gamma secretion upon stimulation. Expression of this factor in the gut mucosa could contribute to up-regulation of the Th1 response in the presence of TNF-alpha, and could be important for mucosal immunoregulation.
Prehn
J L
JL
Cedars-Sinai Inflammatory Bowel Disease Center, Los Angeles, CA 90048, USA.
Landers
C J
CJ
Targan
S R
SR
D000276:Adjuvants, Immunologic / Q000097:blood / Q000494:pharmacology / Q000502:physiology*; D002474:Cell-Free System / Q000378:metabolism; D017077:Culture Media, Conditioned; D016207:Cytokines / Q000502:physiology; D006358:Hot Temperature; D006801:Humans; D007369:Interferon Inducers / Q000494:pharmacology*; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000097:blood / Q000378:metabolism; D016753:Interleukin-10 / Q000096:biosynthesis; D018664:Interleukin-12 / Q000502:physiology; D020382:Interleukin-18 / Q000502:physiology; D015847:Interleukin-4 / Q000096:biosynthesis; D007413:Intestinal Mucosa / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000378:metabolism*; D008213:Lymphocyte Activation; D010835:Phytohemagglutinins / Q000494:pharmacology; D012995:Solubility; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology / Q000502:physiology*
D000276:Adjuvants, Immunologic; D017077:Culture Media, Conditioned; D016207:Cytokines; D007369:Interferon Inducers; D020382:Interleukin-18; D010835:Phytohemagglutinins; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D018664:Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma