Neuroleukin (glucose-6-phosphate isomerase), has been previously cloned from salivary gland messenger RNA. Its biologic activity in saliva is unknown, but potential functions are suggested by the role of neuroleukin in glucose metabolism, neuronal stimulation, immune stimulation, and HIV infection. This 56kDa non-glycosylated enzyme is principally expressed in denervated muscle and has been shown to stimulate neuronal survival, but neuroleukin can be isolated from a variety of sources and is secreted by T cells, B cells, and glioma cells (the central nervous system, MHC Class II- expressing astrocytes). Only dimers of neuroleukin are enzymatically active. In its monomer form, however, neuroleukin retains affinity for phosphoglucose and phosphofructose. Surprisingly, soluble neuroleukin also was found to stimulate immunoglobulin secretion in a manner dependent on T cells and macrophages. In both cases, the mechanism of stimulation was not clear. Neither the involvement of an enzymatic event, nor the monomeric, versus dimeric, state of neuroleukin was determined. The existence of a neuroleukin receptor was postulated. To discover the mechanism of neuroleukin's effect on cellular stimulation, the molecular events during interaction need to be investigated. A possibility is that neuroleukin interacts with membrane components. It has been reported that neuroleukin is associated with microtubules when artificially concentrated by PEG. In this case, neuroleukin was detected by means of substrate hydrolysis which detects dimers of neuroleukin, but not monomers. The possibility was not excluded that the cytoskeletal protein was originally in its monomeric form and that PEG precipitation allowed a concentration-dependent dimerization. Carrying this hypothesis a step further, soluble, cell-free monomers of neuroleukin could have the capacity to form dimers with cell-associated monomers of neuroleukin. The dimerization of neuroleukin would allow conversion of phosphoglucose to phosphofructose to allow transport and enhance this energy pathway, in effect stimulating proliferation. The cell-free monomers would effectively set up a metabolic gradient to attract activated lymphocytes, neurons, and other sensitive cells. In support of this hypothesis, it was found that the enzymatically active form of neuroleukin (the dimer) was inactive as a neurotrophic factor, while reduced neuroleukin (the monomer), demonstrated growth factor activity. The potential for this salivary protein to be involved in recruitment of metabolically active cells provides a new setting in which to interpret oral pathology. Saliva is potent inhibitor of HIV, and the inhibitory components have been partially identified. Additional salivary components are considered to contribute to HIV inhibition suggesting the potential participation of salivary neuroleukin. Interestingly, neuroleukIn neurotrophic activity has been shown to be abrogated by the HIV envelope protein gp120. The converse effect of neuroleukin on HIV infectivity has not been reported. The effect of gp120 on neuroleukin stimulation of immunoglobulin (Ig) secretion has not been investigated. Nor has the effect of gp120 on neuroleukin glucose isomerase activity been investigated. The goal of this proposal is to characterize salivary neuroleukin and dissect its involvement Ig secretion, glucose metabolism, and HIV infectivity by exploiting neuroleukin inhibition by HIV gp120.
| Bristow, C L; Patel, H; Arnold, R R (2001) Self antigen prognostic for human immunodeficiency virus disease progression. Clin Diagn Lab Immunol 8:937-42 |
| Bristow, C L; Di Meo, F; Arnold, R R (1998) Specific activity of alpha1proteinase inhibitor and alpha2macroglobulin in human serum: application to insulin-dependent diabetes mellitus. Clin Immunol Immunopathol 89:247-59 |
| Bristow, C L; Fiscus, S A; Flood, P M et al. (1995) Inhibition of HIV-1 by modification of a host membrane protease. Int Immunol 7:239-49 |
