Modulation of Immune Response by Head Injury - New Insights to Neuroimmune Biology - page 190

Table 10.1 ( Continued)

Experimental Approach IL-1 TNF IL-6

[100]
[17]
[145]
[ 146 ]
[83]

KO mice/transgenic mice [99] [88] [70,71,73]

[19] [19]

[24]

Cytokine-receptor KO mice [98] [89]

Table 10.1 provides an overview of the studies providing evidence for the production and function of cytokines in
patients with severe brain trauma or animal models of TBI. References are also cited describing strategies used for the
neutralization of cytokines in TBI models using specific blockers or general immunosuppressive drugs, as well as the
use of cytokine gene knockouts or transgenic mice. ILinterleukin; TNFtumor necrosis factor; NMDAN-methyl-D-
aspartic acid; ICEIL-1-converting enzyme; EPOerythropoietin; CSFcerebrospinal fluid; KOknockout.

CSF. We also list studies on brain tissue protein and mRNA synthesis and brain micro-
dialysis, as well as experimental, therapeutic, or genetic strategies to inhibit cytokines'
action either to treat secondary brain damage or to further explore their role in such
damage.
Several years ago, we first began to characterize longitudinal patterns of cytokine
production (pro-inflammatory: TNF, IL-6, and IL-8; anti-inflammatory: IL-10, TGF-)
in patients with severe TBI up to 3 weeks postinjury [11,17,40,45,49,53-58] . It became
evident that contrary to what was observed in the rodent brain, the secretion of cyto-
kines in ventricular CSF was elevated over a long period of time, although peaks coin-
cided in the early days after injury. What came as a surprise to us in the early 1990s
was the finding that CSF cytokine measurements exceeded the levels detected in blood
serum, supporting the relatively novel concept that the injured brain has the ability to
mount a profound inflammatory response in which intrathecal cytokines do not origi-
nate via diffusion from the periphery through the BBB but are in fact produced by neu-
ral cells themselves.
For instance, IL-6, the main inducer of the acute phase reaction, was found to
be abundantly released in the CSF of TBI patients. In addition, serum IL-6 corre-
lated with both CSF IL-6 and the levels of acute phase proteins (C-reactive protein,
1-antitrypsin, and fibrinogen), in concomitance with a severe dysfunction of the BBB
[49] . This data from our laboratory suggested that the increased permeability of the
BBB likely allows the diffusion of this cytokine into the bloodstream. Our study found
no association between IL-6 and either better or worse neurological outcome; however,
other groups have shown that IL-6 levels in human brain microdialysate or CSF were
associated with improved recovery, whereas measurements of IL-6 in serum correlated