Several lines of evidence suggest that up-regulation of immune response and alterations of kynurenine pathway function are involved in pathogenesis of schizophrenia. Correlations among clinical status (using PANNS, SANS and SAPS scales) and blood levels of kynurenic acid (KYNA), 3-hydroxykynurenine (3-HK) and levels of selected immunoactive molecules, soluble interleukin-2 receptor (sIL-2R), interferon-α (IFN-α) and IL-4 were analyzed in 51 chronic schizophrenia patients during acute relapse, after four weeks of therapy and at remission. KYNA levels were significantly lower in comparison with controls (N=45) throughout the study, whereas 3-HK did not differ from controls at admission and during therapy, but increased at remission. The KYNA/3-HK ratio and IL-4 levels, but not sIL-2R and IFN-α levels, were consistently decreased in schizophrenia patients at all analyzed time points. KYNA level and KYNA/3-HK ratio measured at admission correlated negatively with the duration of illness, whereas 3-HK level correlated negatively with the improvement of SANS score at discharge. sIL-2R level before treatment was positively linked with number of relapses. In the subgroup of patients with poor response to pharmacotherapy, treated with clozapine later on, initial KYNA level and the ratio KYNA/3-HK correlated negatively with number of relapses. Positive association of sIL-2R level with number of relapses was also evident in this subgroup. Furthermore, among these patients, starting IFN-α level was negatively linked with the improvement of total PANSS score at discharge. Presented here data support the concept of disturbed kynurenine pathway function in schizophrenia and suggest that assessment of KYNA and 3-HK levels during acute relapse might be useful in prediction of response to antipsychotic therapy. Deficit of peripheral KYNA and higher 3-HK levels could be associated with more severe symptoms of schizophrenia. Further studies with larger samples size are needed to validate our results.

Background:Complex interaction of genetic defects with environmental factors seems to play a substantial role in the pathogenesis of inflammatory bowel disease (IBD). Accumulating data implicate a potential role of disturbed tryptophan metabolism in IBD. Kynurenic acid (KYNA), a derivative of tryptophan (TRP) along the kynurenine (KYN) pathway, displays cytoprotective and immunomodulating properties, whereas 3-OH-KYN is a cytotoxic compound, generating free radicals.Methods:The expression of lymphocytic mRNA encoding enzymes synthesizing KYNA (KAT I–III) and serum levels of TRP and its metabolites were evaluated in 55 patients with IBD, during remission or relapse [27 patients with ulcerative colitis (UC) and 28 patients with Crohn’s disease (CD)] and in 50 control individuals.Results:The increased expression of KAT1 and KAT3 mRNA characterized the entire cohorts of patients with UC and CD, as well as relapse–remission subsets. Expression of KAT2 mRNA was enhanced in patients with UC and in patients with CD in remission. In the entire cohorts of UC or CD, TRP levels were lower, whereas KYN, KYNA and 3-OH-KYN were not altered. When analysed in subsets of patients with UC and CD (active phase–remission), KYNA level was significantly lower during remission than relapse, yet not versus control. Functionally, in the whole groups of patients with UC or CD, the TRP/KYN ratio has been lower than control, whereas KYN/KYNA and KYNA/3-OH-KYN ratios were not altered. The ratio KYN/3-OH-KYN increased approximately two-fold among all patients with CD; furthermore, patients with CD with relapse, manifested a significantly higher KYNA/3-OH-KYN ratio than patients in remission.Conclusion:The presented data indicate that IBD is associated with an enhanced expression of genes encoding KYNA biosynthetic enzymes in lymphocytes; however, additional mechanisms appear to influence KYNA levels. Higher metabolic conversion of serum TRP in IBD seems to be followed by the functional shift of KYN pathway towards the arm producing KYNA during exacerbation. We propose that KYNA, possibly via interaction with aryl hydrocarbon receptor or G-protein-coupled orphan receptor 35, may serve as a counter-regulatory mechanism, decreasing cytotoxicity and inflammation in IBD. Further longitudinal studies evaluating the individual dynamics of TRP and KYN pathway in patients with IBD, as well as the nature of precise mechanisms regulating KYNA synthesis, should be helpful in better understanding the processes underlying the observed changes.

The link between the kynurenine pathway and immunomodulatory molecules—fractalkine and soluble intercellular adhesion molecule-1 (sICAM-1)—in anorexia nervosa (AN) remains unknown. Fractalkine, sICAM-1, tryptophan (TRP), kynurenine (KYN), neuroprotective kynurenic acid (KYNA), neurotoxic 3-OH-kynurenine (3-OH-KYN), and the expression of mRNA for kynurenine aminotransferases (KAT1-3) were studied in 20 female patients with restrictive AN (mostly drug-free, all during first episode of the disease) and in 24 controls. In AN, serum fractalkine, but not sICAM-1, KYNA, KYN, TRP or 3-OH-KYN, was higher; ratios TRP/KYN, KYN/KYNA, KYN/3-OH-KYN and KYNA/3-OH-KYN were unaltered. The expression of the gene encoding KAT3, but not of genes encoding KAT1 and KAT2 (measured in blood mononuclear cells), was higher in patients with AN. In AN, fractalkine positively correlated with TRP, while sICAM-1 was negatively associated with 3-OH-KYN and positively linked with the ratio KYN/3-OH-KYN. Furthermore, TRP and fractalkine were negatively associated with the body mass index (BMI) in AN. Expression of KAT1, KAT2 and KAT3 did not correlate with fractalkine, sICAM-1 or BMI, either in AN or control. Increased fractalkine may be an independent factor associated with the restrictive type of AN. Excessive physical activity probably underlies increased expression of KAT3 observed among enrolled patients. Further, longitudinal studies on a larger cohort of patients should be aimed to clarify the contribution of fractalkine and KAT3 to the pathogenesis of AN.

Cel pracyCelem pracy było 1) porównanie poziomu ekspresji genów apoptozy BAX, BCL2, BIRC6, CASP3, CASP9 u pacjentów ze schizofrenią i w grupie kontrolnej oraz 2) określenie powiązań pomiędzy poziomem ekspresji genów a parametrami morfologicznymi krwi obwodowej oraz nasileniem objawów psychopatologicznych.MetodaDo badania włączono 21 pacjentów z rozpoznaniem schizofrenii wg ICD-10 oraz 26 zdrowych osób. Oceniano ekspresję genów w limfocytach krwi obwodowej, parametry laboratoryjne oraz nasilenie objawów psychopatologicznych za pomocą skali PANSS.WynikiEkspresja genu BCL2 i genu CASP3 była istotnie wyższa u pacjentów ze schizofrenią w porównaniu z grupą kontrolną. W grupie pacjentów ze schizofrenią wykazano istotną dodatnią korelację poziomu ekspresji genu BAX z liczbą neutrofili, limfocytów i monocytów oraz nasileniem objawów negatywnych (PANSS-N), zaś genu BCL2 i CASP9 z liczbą monocytów, natomist genu CASP3 z liczbą limfocytów.Wnioski1. Istotnie wyższa ekspresja genów BCL2 i CASP3 pacjentow ze schizofrenią w porównaniu do grupy kontrolnej dowodzi nasilenia procesu apoptozy, wpisując się w teorię zwiększonej apoptozy w patofizjologii schizofrenii. 2. Istotne korelacje pomiędzy ekspresją genu BAX a parametrami układu białokrwinkowego (liczbą leukocytów, neutrofili, limfocytów, monocytów) w grupie pacjentów ze schizofrenią, sugerują związek z dysregulacją immunologiczną i potwierdzają obecność apoptozy w limfocytach krwi obwodowej. 3. Ekspresja genu BAX może być wskaźnikiem nasilenia objawów negatywnych w schizofrenii. 4. Analiza interkorelacji ekspresji badanych genów wskazuje, że najaktywniejszymi genami w procesie apoptozy w badanej grupie były BAX i CASP3.

Background and objectives: Inflammatory bowel disease (IBD) mainly includes Crohn’s disease (CD) and ulcerative colitis (UC). Both conditions are associated with an exacerbated intestinal immune response to harmless stimuli, leading to upregulation of pro-inflammatory mediators. Materials and Methods: The subjects of the study were 55 patients with IBD. The control group consisted of 35 healthy subjects. The researched material consisted of peripheral blood lymphocytes collected from the subjects. Expression of the genes BAX, BCL2, CASP3 and CASP9 was assessed at the mRNA level in the peripheral blood lymphocytes of patients with ulcerative colitis and Crohn’s disease relative to the healthy subjects. The expression of the genes was determined by rtPCR using TaqMan probes specific for these genes. Results: The group of patients diagnosed with CD had statistically significantly higher expression of the genes BAX (p = 0.012), BCL2 (p = 0.022), CASP3 (p = 0.003) and CASP9 (p = 0.029) than healthy subjects. Expression of BAX, BCL2, CASP3 and CASP9 in UC patients in the active phase of the disease was significantly lower than in patients in remission: BAX (p = 0.001), BCL2 (p = 0.038) and CASP9 (p = 0.007). In patients with UC, the BAX/BCL2 ratio was significantly correlated (r = 0.473) with the duration of the disease. In the group of CD patients treated biologically, a significantly lower BAX/BCL2 ratio was demonstrated than in patients that were not biologically treated. Conclusions: Our research has shown a simultaneous increase in the expression of the anti-apoptotic BCL2 gene and the proapoptotic BAX gene, which suggests the dysregulation of apoptosis mechanisms in IBD. Significantly higher expression of BAX and BCL2 in UC patients in remission as compared to CD may suggest differences in these diseases in terms of prognosis and treatment. Our results may suggest that an underlying imbalance in factors controlling apoptosis in peripheral blood lymphocytes may be the response of the immune system to inflammation of the intestinal mucosa. Modulation of apoptosis may become an important therapeutic mechanism in IBD.