Modulation of Immune Response by Head Injury - New Insights to Neuroimmune Biology - page 193

In TBI, a large number of studies have demonstrated up-regulated expression of
IL-1 mRNA and protein from the early hours up to days after focal and diffuse TBI
in animal models. Increase of IL-1 was detected using a variety of molecular tech-
niques, including immunohistochemistry, microarray, multiplex, and microdialysis;
and was associated with BBB dysfunction, hippocampal cell death, and motor defi-
cit [64,66-69,82,93-95] . Although IL-1 promotes the synthesis of neurotrophic fac-
tors, this cytokine is generally believed to be neurotoxic in neuropathology, as shown
by inhibitory experiments utilizing IL-1ra which improved outcome when injected
peripherally or centrally after ischemia or TBI [96] . In contrast, one study has shown
that transplantation of fibroblasts transfected to release IL-1ra into the contusion,
although improving outcome, actually reduced NGF production [97] . In another study,
mice lacking IL-1 receptor expression exhibited reduced glial activation and decreases
in Cox-2, IL-1, and IL-6, though TNF and NGF remained unchanged [98] . In addi-
tion, IL-1ra transgenic mice showed attenuated acute IL-1, TNF, and IL-6 levels after
TBI, coinciding with improved neurological recovery [99] . Preclinical animal experi-
ments that tested immune suppressive drugs such as minocycline or erythropoietin
(EPO) attributed the neuroprotective mechanisms of these compounds to the reduction
of brain IL-1 synthesis after TBI [17,83,100] .
Although IL-1 can be difficult to measure in human fluids, there are several stud-
ies reporting elevation of IL-1 concentrations in CSF or microdialysates of TBI
patients [101-108] . In pericontusional brain tissue acquired from patients undergoing
surgery after TBI, IL-1 expression has been shown using both immunohistochemistry
and in situ hybridization, and up-regulation of IL-1 was found in both the acute and
delayed stages [105] . In some clinical studies, a rise in IL-1 levels seems to correlate
with poor neurological outcome [103,109] . However, dissociation between improve-
ment of outcome and IL-1 increase was suggested following mild hypothermia in
pediatric TBI. Although hypothermia successfully decreased intracranial pressure in
this patient population, it did not attenuate enhanced production of IL-1, nor of IL-6
or IL-10, in ventricular CSF [108] .
10.6 Role of Chemokines in TBI
Chemokines, or chemo tactic cyto kines , contribute to neuroinflammation following TBI
by initiating the recruitment of peripheral leukocytes into the injured brain parenchyma.
The function of these mediators in the migration and activation of leukocyte subsets
is well established; however, their relative contributions to both physiological homeo-
stasis and pathological conditions are still being identified. Chemokine expression
is not restricted to hematopoietic cells; rather, both glia and neurons are capable
of secreting a range of chemokines, and constitutively express a wide variety of
chemokine receptors [110,111] . In the CNS, chemokine actions are crucial, not only
in disease states, but also in neuronal migration during development, cell prolifera-
tion, protection against neuronal cytotoxicity, and intercellular communication. Gene
deficiency studies have clearly demonstrated that several chemokines act as vital,
nonredundant mediators in inflammatory responses, such as that resulting from TBI.