Role of the Sympathetic Nervous System in Immunity - New Insights to Neuroimmune Biology - page 92

NE or a  2 AR agonist induced a decrease in IFN- production, primarily due to a
decrease induced in IL-12 production by APC [80,81,98-100] . These findings indi-
cate that a decrease in IL-12 induced by either NE or a  2 AR agonist prevented Th1
cell differentiation, resulting in a possible shift to Th2 cell development.
The clinical relevance of such an effect of NE on the level of IFN- produced by
Th1 cells is unclear. When human HIV-infected PBMCs were exposed in vitro to
NE, stimulation of the  2 AR decreased production of IFN-, IL-10, and IL-4, but
enhanced HIV replication in T cells [106] , suggesting that NE stimulation of the
 2 AR on T cells may enhance HIV pathogenesis by inhibiting the production of all
cytokines that would prevent HIV replication. Also, it has been reported that T cells
infiltrating the inflamed synovium of rheumatoid arthritis (RA) patients and mice are
of the Th1 cell phenotype and produce IFN- [107,108] . In addition, the administra-
tion of a  2 AR antagonist prior to, and during, the disease process appears to delay
the onset and reduce the severity of joint injury [109] , suggesting that NE stimula-
tion of the  2 AR on either a naïve CD4 T cell or a Th1 cell itself might play a role
in increasing IFN- and thereby exacerbate this autoimmune disease process [110] .
This finding was recently expanded to the CD4CD25 T cell subpopulation of
cells isolated from collagen-immunized mice. When these T cells were isolated from
immunized NE-depleted mice and adoptively transferred to mice with established
collagen-induced arthritis, the cells secreted less cytokine and decreased disease
severity in comparison to cells from immunized NE-intact mice, suggesting that NE
may increase disease severity by increasing cytokine release in the early phases of
disease induction [110,111] .
In contrast, it was thought that NE has no effect on Th2 cell activity because the
Th2 cell did not express the  2 AR [51] . While the effect of NE and  2 AR stimula-
tion on naïve T cell differentiation to Th2 cells, and the resulting function of the Th2
cell, remain unknown, one study suggested that NE may hinder the development of
a normal Th2 response, because cells from an immunized NE-deficient mouse pro-
duced significantly higher levels of IL-2 and IL-4 following reactivation in vitro as
compared to cells isolated from immunized NE-intact control mice [112] . However,
an effect on Th2 cell activity could be caused indirectly by a NE-mediated effect on
another cell that influences Th2 cell activity. For example, in mice receiving thermal
burn injuries, elevated plasma NE levels were associated with increased macrophage
production of the Th2 chemokine CCL2 and the subsequent development of a pre-
dominant Th2-like response, which was prevented by NE depletion [113,114] . This
finding suggested that NE regulated macrophage chemokine secretion and the sub-
sequent increase in Th2 cell accumulation at the site of injury, which possibly might
influence susceptibility to infections after a thermal burn, as has been described pre-
viously [115] .
Thus, the effect of NE and  2 AR stimulation on CD4 T cell activity remains
controversial. There appears to be an inhibitory effect on naïve CD4 T cell IL-2
production, but an enhancing effect on the amount of IFN- that is produced by Th1
cells that develop. Therefore, NE and  2 AR stimulation of a naïve CD4 T cell does
not appear to affect the number of Th1 cells that develop, but appears to affect the
amount of IFN- secreted by those Th1 cells. The effect of NE on effector Th1 and