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Altered leukotriene generation in leukocytes from cystinotic children
G Pintos-Morell1, P Salem, G Jean
1University Hospital Germans Trias i Pujol, Badalona, Spain.
Insights
Children with cystinosis exhibit elevated leukotriene (LT) C4 production in polymorphonuclear leukocytes (PMNL). Cysteamine treatment reduces this heightened LTC4 generation, suggesting metabolic changes in cystinosis influence eicosanoid biosynthesis.
Area of Science:
- Biochemistry
- Immunology
- Pediatrics
Background:
- Infantile cystinosis is a lysosomal storage disorder characterized by cystine accumulation.
- Eicosanoid metabolism, including leukotriene synthesis, plays a role in inflammatory processes.
- Polymorphonuclear leukocytes (PMNL) are key immune cells involved in inflammation.
Purpose of the Study:
- To investigate leukotriene production in PMNL from children with cystinosis.
- To determine the effect of cysteamine treatment on leukotriene generation in cystinotic PMNL.
- To explore the relationship between metabolic abnormalities in cystinosis and eicosanoid biosynthesis.
Main Methods:
- In vitro stimulation of PMNL with ionophore A 23187.
- Quantification of leukotriene C4 (LTC4) and leukotriene B4 (LTB4) production.
- Comparison of LTC4 and LTB4 levels in PMNL from untreated cystinotic children, control children, and normal adults.
- Assessment of LTC4 production in PMNL from cystinotic children treated with cysteamine and after cessation of treatment.
Main Results:
- PMNL from untreated cystinotic children showed significantly increased LTC4 generation compared to controls and normal adults.
- LTB4 production was decreased in PMNL from untreated cystinotic children.
- Cysteamine treatment reduced LTC4 production in cystinotic PMNL, with levels increasing upon treatment cessation.
- Eosinophil counts were similar across all groups, excluding them as a factor in increased LTC4.
Conclusions:
- Metabolic abnormalities in infantile cystinosis favor LTC4 biosynthesis in PMNL.
- Cysteamine, by reducing intracellular cystine, modulates LTC4 production.
- These findings highlight a potential link between cystinosis pathophysiology and inflammatory mediator generation.
Abstract:
Upon in vitro stimulation with 10 microM ionophore A 23187 for 5 min at 37 degrees C, the generation of leukotriene (LT) C4 in polymorphonuclear leukocytes (PMNL) from nine untreated cystinotic children was significantly increased compared with that in eight control children (p < 0.01) and 25 normal adults (p < 0.001) (417.4 +/- 70.0 versus 177.0 +/- 30.9 and 164.9 +/- 19.5 pmol/l x 10(7) cells, respectively). Concomitantly with the increased generation of LTC4, LTB4 production in PMNL from untreated cystinotic children was decreased compared with controls, whereas the total amount of LTA4 derivatives was similar in the three groups. The increase in LTC4 production was not related to the number of eosinophils present in the PMNL preparations from cystinotic children, which was similar to that of control subjects. PMNL from cystinotic children treated with cysteamine, an aminothiol compound that decreases the intracellular cystine content, generated smaller amounts of LTC4 upon ionophore A 23187 stimulation than PMNL from untreated cystinotic children. In addition, abrogation of the cysteamine treatment for 3 or 4 d led to an increase in LTC4 production. These findings suggest that the metabolic abnormalities taking place in infantile cystinosis may favor the biosynthesis of LTC4 from PMNL.