G. Kaplanski et al., INTERLEUKIN-1 INDUCES INTERLEUKIN-8 SECRETION FROM ENDOTHELIAL-CELLS BY A JUXTACRINE MECHANISM, Blood, 84(12), 1994, pp. 4242-4248
Inflammation is characterized by migration of neutrophils through the
endothelium, and the chemokine interleukin-l (IL-8) appears to be invo
lved. We asked whether adherence of cells bearing a membrane-form of i
nterleukin 1 (IL-1) induces IL-8 secretion from human umbilical vein e
ndothelial cells (HUVEC) and fibroblasts. Human peripheral blood monon
uclear cells (PBMC) were stimulated with endotoxin for 12 hours and th
en fixed for 4 hours with paraformaldehyde. When these cells were adde
d to HUVEC or fibroblasts, IL-8 production was induced. This stimulati
on by fixed PBMC was attributed to IL-l, because pretreatment of HUVEC
or fibroblasts with IL-l receptor antagonist (1L-1Ra) reduced the ind
uction by 95% and 80%, respectively, P < .005. Using anti-ll-l alpha m
onoclonal antibodies, reduction was complete, whereas anti-IL-l beta h
ad no effect. IL-1 alpha was shown on the surface of monocytes by fluo
rescence-activated cell sorter (FAGS) analysis. Blockade of IL-l recep
tors on PBMC did not affect the activity of membrane-associated IL-1 a
lpha, indicating that IL-l is not anchored to the membrane through its
receptors. However, PBMC treated with D-mannose before fixation resul
ted in a loss of activity; this loss of activity was associated with r
elease of IL-l1 alpha, not IL-1 beta, into the supernatant. Thus, anch
oring of IL-1 alpha to the membrane may be via a lectin or mannose rec
eptor-like interaction. Blockade of membrane IL-1 alpha required a 30-
fold and fivefold excess of IL-1Ra compared with the amount required t
o block soluble IL-1 beta and IL-1 alpha, respectively. We conclude th
at the fixed PBMC IL-8 inducing activity is almost entirely caused by
IL-l, that this represents lL-1 alpha bound to a surface lectin or man
nose receptor on the monocyte, and that it functions in inflammation v
ia juxtacrine interactions. (C) 1994 by The American Society of Hemato
logy.