Physiologic concentrations of TNFalpha and IL-1beta released from reperfused human intestine upregulate E-selectin and ICAM-1.
Intestinal ischemia-reperfusion (I/R) causes local and distant tissue injury via neutrophil (PMN) activation and adhesion. Endothelial cell adhesion molecules (E-selectin, ICAM-1) mediate the adhesion and transmigration of PMN in the microcirculation. Expression of these receptors is influenced by cytokines. To determine the physiologic concentrations of two specific cytokines involved in I/R, tumor necrosis factor (TNF) and interleukin-1 (IL-1), human intestinal segments were exposed to 30 min of ischemia followed by reperfusion. Venous effluent samples were obtained; enzyme immunoassays measured maximum concentrations of TNF (30.5 +/ 1.0 pg/ml) and IL-1 (59.0 +/- 6.0 pg/ml). Cultured human endothelial cells were then exposed to physiologic concentrations of human recombinant TNF (10 pg/ml) and IL-1 (10 pg/ml), individually and in combination. Flow cytometric analysis of receptor expression demonstrated upregulation of E-selectin as early as 2 hr (P < 0.05) with maximum effects at 4 hr. At 4 hr, E-selectin expression (% shift from baseline) was greater with TNF and IL-1 combined (50.9 +/- 2.9, P < 0.01) than with either cytokine alone (TNF 34.6 +/- 4.0; IL-1 23.5 +/- 4.0, P < 0.01). ICAM-1 receptor expression began at 4 hr with maximum effects at 24 hr. ICAM-1 expression after TNF and IL-1 exposure (15.4 +/- 1.3, P < 0.001) was also greater than TNF (10.9 +/- 0.3, P < 0.01) or IL-1 (3.1 +/- 1.5) alone. TNF and IL-1 are present in venous effluent in concentrations capable of increasing PMN adhesion in the microcirculation. These findings support a role for these cytokines in local and distant organ injury from I/R. Since combined effects are greater than either cytokine alone, antagonism of both TNF and IL-1 may be required for a therapeutic benefit in clinical applications.
Wyble
C W
CW
Department of Surgery, University of Chicago, Illinois 60637, USA.
Desai
T R
TR
Clark
E T
ET
Hynes
K L
KL
Gewertz
B L
BL
D002478:Cells, Cultured; D019040:E-Selectin / Q000096:biosynthesis*; D004730:Endothelium, Vascular / Q000502:physiology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis*; D007375:Interleukin-1 / Q000494:pharmacology* / Q000502:physiology*; D007421:Intestine, Small / Q000098:blood supply / Q000502:physiology*; D007511:Ischemia; D015424:Reperfusion / Q000295:instrumentation / Q000379:methods; D015427:Reperfusion Injury / Q000276:immunology / Q000503:physiopathology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology* / Q000502:physiology*; D014471:Umbilical Veins
D019040:E-Selectin; D007375:Interleukin-1; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1