The role of CD18 in IL-8 induced dermal and synovial inflammation.
1. The intradermal administration of endothelial IL-8 (IL-8(1-77) or monocyte derived IL-8 (IL-8(1-72) to rabbits produced a concentration-dependent increase in plasma extravasation and an accumulation of polymorphonuclear leukocytes (PMNs) when measured over a 3 h time period. When plasma extravasation and PMN accumulation were measured over a 30 min time period no significant increases in PMN accumulation or plasma extravasation were observed in response to IL-8 alone. However, under these conditions, the addition of prostaglandin E2 (100 pmol) produced a significant potentiation of IL-8-induced plasma extravasation. There was no significant difference between the biological activities of IL-8(1-77) and IL-8(1-72). 2. Plasma extravasation and PMN accumulation induced by IL-8 were inhibited in rabbits pretreated with the monoclonal antibody designated IB4 (1 mg kg-1, i.v.) directed against the common beta chain (CD18) of the leukocyte integrins. 3. The intra-articular administration to rabbits of IL-8(1-77) (1 nmol) resulted 24 h later in the appearance of a mixed population of leukocytes (PMNs and mononuclear cells) in synovial lavage fluid. Biochemical analyses revealed the presence of an increased level of sulphated proteoglycans (sPG) and of the metalloproteinase stromelysin. Pretreatment of rabbits with IB4 (3 mg kg-1, i.v.) inhibited the accumulation of PMNs but had no effect on the mononuclear infiltrate nor on the levels of sPG or stromelysin. 4. The intradermal or intra-articular injection of E. coli-derived endotoxin induced similar inflammatory changes to those observed with IL-8.The possibility that the biological activities of IL-8 were attributable to minor contamination with endotoxin is unlikely for two reasons. Firstly, biological effects of endotoxin were observed at levels greater than that contained in the IL-8 preparation. Secondly,reduction of the endotoxin content of the IL-8 preparation by a factor of 10 did not produce a concomitant reduction in the observed biological activity of the IL-8.
Department of Cellular & Molecular Pharmacology, Merck Sharp & Dohme Research Laboratories, Rahway, N.J. 07065-0900.
M J
MJ
Forrest
G J
GJ
Eiermann
R
R
Meurer
L A
LA
Walakovits
D E
DE
MacIntyre
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D015703:Antigens, CD / Q000502:physiology*; D018821:CD18 Antigens; D003872:Dermatitis / Q000503:physiopathology*; D004731:Endotoxins / Q000032:analysis; D004926:Escherichia coli / Q000378:metabolism; D005260:Female; D016209:Interleukin-8 / Q000032:analysis / Q000502:physiology*; D019278:Matrix Metalloproteinase 3; D008666:Metalloendopeptidases / Q000378:metabolism; D009504:Neutrophils / Q000276:immunology; D011509:Proteoglycans / Q000378:metabolism; D011817:Rabbits; D013582:Synovial Fluid / Q000166:cytology / Q000378:metabolism; D013585:Synovitis / Q000503:physiopathology*; D007507:Therapeutic Irrigation
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D018821:CD18 Antigens; D004731:Endotoxins; D016209:Interleukin-8; D011509:Proteoglycans; D008666:Metalloendopeptidases; D019278:Matrix Metalloproteinase 3