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The proinflammatory cytokine response to coagulation and endotoxin in whole
blood
K Johnson, L Aarden, Y Choi, E De Groot and A Creasey
Department of Cell Biology, Chiron Corp, Emeryville, CA, 94608, USA.
Acute inflammatory illnesses, including the sepsis syndrome, often include
a component of coagulation. A human whole blood culture system was
developed so that the relationship between coagulation activation and
cytokine responses in the presence or absence of lipopolysaccharide (LPS)
could be evaluated. In the absence of LPS stimulation, coagulation
activation resulted in a novel pattern of cytokine production. During a
4-hour culture of coagulating blood, significant production of
interleukin-8 (IL-8; >2,000 pg/mL) was observed, whereas other
proinflammatory cytokines including IL-1 beta, IL-6, or tumor necrosis
factor a were undetectable or less than 35 pg/mL. The cytokine profile was
distinct from that of fully anticoagulated, LPS-stimulated blood, which
showed levels of all the indicated proinflammatory cytokines > or =
2,000 pg/mL over the same time period. Over 24 to 48 hours, the
coagulation-induced cytokine response was characterized by marked and
sustained IL-8 production, limited IL-6 generation (with kinetics delayed
relative to IL-8), and minimal or undetectable tumor necrosis factor alpha
levels. The magnitude of the whole blood IL-8 response correlated with the
level of coagulation activation as determined by measurement of
thrombin-antithrombin III complex formation. The combined stimuli of
coagulation activation and LPS challenge induced a synergistic enhancement
of IL-8 production but not of IL-6. Coagulation-induced cytokine production
and the synergistic production of IL-8 by coagulation and LPS could be
attenuated by hirudin or tissue factor pathway inhibitor (TFPI). Studies to
elucidate mechanisms implicated (1) the TFPI third Kunitz and
carboxy-terminus as important structural components for TFPI regulation of
coagulation activation and (2) thrombin as a candidate mediator of the
mononuclear cell cytokine response to coagulation activation. In summary, a
unique aspect of the crosstalk between the coagulation and cytokine
cascades in whole blood is shown with the identification of IL-8 as a key
proinflammatory participant.
Volume 87,
Issue 12,
pp. 5051-5060,
06/15/1996
Copyright © 1996 by The American Society of Hematology
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