The effects of brain infusion of human immunodeficiency virus glycoprotein (gp120) and peripheral L S on splenic macrophage IL-1B and TNFA and splenic sympathetic nerve activity

It has been shown previously that immune cells produce cytokines such as interleukin-1$\\beta$ (IL-1$\\beta$) and tumor necrosis factor $\\alpha$ (TNF$\\alpha$) which can signal the central nervous system and result in immune suppression. It has been demonstrated in our lab that an immune challenge, bacterial lipopolysaccharide (LPS) or endotoxin, can activate central autonomic regulatory regions and pathways, and increase sympathetic input to the spleen. In addition, splenic macrophage function has been shown to be regulated by the splenic nerve, and that the sympathetic signal is tonically immunosuppressive and further suppression can be centrally induced. Our previous data indicated that the HIV-1 coat protein, gp120, may disrupt the neural-immune regulatory circuit and our present hypothesis is that gp120 produces autonomic dysregulation which may result in a cytokine environment in the spleen that enhances HIV replication in early infection. gp120, infused into brain ventricles, has been shown to enhance splenic macrophage function, as measured by macrophage cytokine production after LPS stimulation in vitro, rather than suppressing function as do intracerebral ventricular cytokines. However, similar to cytokines or LPS, gp120 does elevate plasma corticosterone. In addition, gp120, coinfused with $\\alpha$-msh, attenuated the increase in splenic NE turnover produced by $\\alpha$-MSH, which is thought to play a role in the sympathetic down regulatory mechanism. Yet, gp120 had no effect on NE turnover when gp120 was infused alone. This data suggested that gp120 may disrupt sympathetic inhibition of splenic macrophage activity. The present study sought to observe in vivo the effect of central gp120 (4$\\mu$g icv) on LPS ("low dose" 0.1$\\mu$g iv) stimulated splenic cytokine mRNA production via Northern Blot analysis of the splenic cytokine mRNAs in rats. Immunocytochemistry was also used to examine TNF$\\alpha$ protein in vivo. It was expected that a small peripheral dose of LPS would result in increased cytokine mRNA expression and that central gp120 would significantly enhance this expression. The hypothesis was confirmed as gp120 did significantly increase the levels of both TNF$\\alpha$ (p $<$.05) and IL-1$\\beta$ (p $<$.025) mRNAs. This enhancement is consistent with our previous findings that central gp120 significantly increased splenic macrophage production of cytokines after low dose LPS stimulation in vitro. TNF$\\alpha$ protein was not significantly elevated but a trend was apparent and the levels were significantly correlated with the mRNA levels (p $<$.0001). As seen previously, plasma corticosterone levels were significantly elevated (p $<$.0001) following central gp120 and low dose LPS relative to vehicle injected controls, but there was no difference in plasma catacholamines, suggesting no change in sympathetic activity. The present study also sought to examine the effect of centrally infused gp120 on the LPS ("high dose" 100$\\mu$g iv) induced increase in splenic nerve electrical activity in adult male rats. It was predicted that gp120 would attenuate the LPS induced increase in splenic nerve activity. With regard to this latter hypothesis, no inhibition was observed under the conditions of the present experiment. Although gp120 did not attenuate the increase in sympathetic nerve activity induced by intravenous LPS, this does not directly conflict with the ability of gp 120 to block the increase in NE turnover produced by central $\\alpha$-MSH injection. Overall, these data provide further evidence that gp120 acts in the brain to alter the splenic cytokine environment by attenuating the suppressive signal provided by the sympathetic nervous system.

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