EDITORIAL FOCUS
Use of knockouts to define sequential steps on a pathway
to organ injury
Focus on "Essential role for IL-6 in
postresuscitation inflammation in hemorrhagic shock"
Joseph S.
Solomkin
Department of Surgery, University of Cincinnati College of
Medicine, Cincinnati, Ohio 45267-0558
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ARTICLE |
A VARIETY of both pro- and
anti-inflammatory mediators can be detected in plasma taken from
otherwise healthy individuals suffering any one of a variety of acute
conditions, including major injury with hemorrhagic shock
(3). Recent attention has focused on interleukin (IL)-6
because of the known effects of IL-6 on the function of inflammatory
cells and because IL-6 levels correlate with subsequent clinical course
(5). An understanding of the biological effects of IL-6 is
complicated by the role of soluble IL-6R
in conferring
responsiveness to cells that do not ordinarily express this receptor.
There are several difficulties in establishing cause-effect
relationships for these events. Binding to various proteins or cell
receptors may modulate bioactivity of the mediator under study. One
function of shed receptors in the vascular space or site of
inflammation may be to serve as a sink for its ligand, abrogating
ligand bioactivity by binding. Furthermore, infusion of mediators may
actually downregulate the inflammatory response to subsequently
encountered stimuli. This has, for example, been well studied with IL-8
(3). This may occur through a variety of mechanisms,
including loss of cell surface receptors for the ligand under study and
induction of anti-inflammatory mediators (1). In
experiments in which mediator infusion induces organ injury, it often
is not known whether this is a direct effect of the specific mediator
or a more distal effect of sequential mediator and cellular activation.
A study by Meng et al., the current article in focus (Ref.
4, see p. C343 in this issue), provides a template for
addressing the role of specific mediators in the evolution of systemic
inflammatory disease. The basis for their research was the paradoxical
observation that locally applied IL-6 induced neutrophil infiltration
and lung injury, while systemic infusion of IL-6 reduced inflammation and injury. With the use of IL-6 knockouts and histological and functional assays of lung and liver, they demonstrated that knockout animals experienced less organ injury than wild-type animals. This
supports the notions that the proinflammatory consequences of locally
generated IL-6 are central to organ injury in this model of hemorrhagic
shock and that this local effect predominates over the
anti-inflammatory effects of intravascular IL-6.
Meng et al. used specific assays of hepatocyte activation, Stat3
activation, and increased nuclear factor-
B activity to identify at
least one element of the reduced organ injury seen in the knockouts.
The finding of these events in wild-type animals but not in the
knockouts provides a mechanistic connection between IL-6 activity and
the cellular activation required for organ injury.
These findings also implicate IL-6 as a proximal mediator of injury.
The next step in this work would be to demonstrate that more distal
elements are persistently functional. This will serve to further
clarify the participation of local IL-6 as a neutrophil activating substance.
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FOOTNOTES |
Address for reprint requests and other correspondence: J. S. Solomkin, Dept. of Surgery, Univ. of Cincinnati College of Medicine, 231 Bethesda Ave., Cincinnati, OH 45267-0558 (E-mail:
joseph.solomkin{at}uc.edu).
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REFERENCES |
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Am J Physiol Cell Physiol 280(2):C237-C238
0363-6143/01 $5.00
Copyright © 2001 the American Physiological Society