Differential effects of kynurenine and tryptophan treatment on quinolinate immunoreactivity in rat lymphoid and non-lymphoid organs

Abstract

Quinolinate is a tryptophan metabolite and an intermediary in nicotinamide adenine dinucleotide (NAD+) synthesis in hepatocytes. Kynurenine is an upstream metabolite in the same biochemical pathway. Under normal physiological conditions, kynurenine is thought to be produced primarily in the liver as an NAD+ precursor. However, during immune stimulation or inflammation, numerous extrahepatic tissues convert systemic tryptophan to kynurenine, and its concentration subsequently rises dramatically in blood. The fate and role of extrahepatic kynurenine are uncertain. In order to begin addressing this question, the present study was performed to determine which cell types can produce quinolinate from either systemic tryptophan or kynurenine. By using highly specific antibodies to protein-coupled quinolinate, we found that intraperitoneal injections of tryptophan led to increased quinolinate immunoreactivity primarily in hepatocytes, with moderate increases in tissue macrophages and splenic follicles. In contrast, intraperitoneal injections of kynurenine did not result in any significant increase in hepatocyte quinolinate immunoreactivity, but rather led to dramatic increases in immunoreactivity in tissue macrophages, splenic white pulp, and thymic medulla. These findings suggest that hepatocytes do not make significant use of extracellular kynurenine for quinolinate or NAD+ synthesis, and that, instead, extrahepatic kynurenine is preferentially metabolized by immune cells throughout the body. The possible significance of the preferential metabolism of kynurenine by immune cells during an immune response is discussed.

Quinolinate as a Marker for Kynurenine Metabolite Formation and the Unresolved Question of NAD+ Synthesis During Inflammation and Infection

“…While it is likely that Quin-IR cells express active kynurenine pathway enzymes from IDO to QPRT, it is possible that not all cells require IDO expression. Our experiments involving tryptophan and kynurenine loading in rats indicate that many cells of the immune system avidly take up kynurenine and convert it to Quin in <3 h (29). This suggests that cells such as fibroblasts that release kynurenine (45) may feed Quin synthesis and NAD + production in other cell types.…”

“…The digital images presented here were generated from archival slides prepared previously and include material from both published (25)(26)(27)(28)(29) and unpublished studies. The methods used for the production, purification, and characterization of the polyclonal Quin antibodies have been described previously (26).…”

High-affinity uptake of kynurenine and nitric oxide-mediated inhibition of indoleamine 2,3-dioxygenase in bone marrow-derived myeloid dendritic cells

“…Moffett et al have shown that intraperitoneal injections of Kyn did not result in any significant increase in hepatocyte immunoreactivity with quinolinate-specific antibody, but rather led to dramatic increase in immunoreactivity in tissue macrophages, splenic white pulp, and thymic medulla [43,44]. Quinolinic acid formation was also induced most strongly in spleen by systemic immune stimulation with pokeweed mitogen [45].…”

Mechanistic perspective on the relationship between pyridoxal 5'-phosphate and inflammation

“…In mice, kynurenine and 3‐hydroxykynurenine and xanthurenic acid, which is a product of a PLP‐dependent reaction, contribute to development of immunotolerence in airway inflammation in allergic asthma . Additional evidence for involvement of PLP‐dependent reactions of the kynurenine pathway in immune response comes from the accumulation of quinolate (Figure ) at micromolar concentrations or greater in lymphoid tissues and macrophages during immune response . Thus, it appears that tryptophan degradation via PLP‐dependent reactions is involved in developing immune tolerance, suppression of inflammation, and reducing tissue damage due to immune response.…”