The Telomere/Telomerase System in Chronic Inflammatory Diseases. Cause or Effect?

Telomeres are specialized nucleoprotein structures located at the end of linear chromosomes and telomerase is the enzyme responsible for telomere elongation. Telomerase activity is a key component of many cancer cells responsible for rapid cell division but it has also been found by many laboratories around the world that telomere/telomerase biology is dysfunctional in many other chronic conditions as well. These conditions are characterized by chronic inflammation, a situation mostly overlooked by physicians regarding patient treatment. Among others, these conditions include diabetes, renal failure, chronic obstructive pulmonary disease, etc. Since researchers have in many cases identified the association between telomerase and inflammation but there are still many missing links regarding this correlation, the latest findings about this phenomenon will be discussed by reviewing the literature. Our focus will be describing telomere/telomerase status in chronic diseases under the prism of inflammation, reporting molecular findings where available and proposing possible future approaches

Determination of telomerase activity on molecular level in b-lymphocytes from patients suffering from renal failure and its correlation with immunologic and biochemic factors

Telomeres are specialized nucleoprotein structures located at the extremities of linear chromosomes which become shortened after each round of cell division. After several cell duplications, telomere length becomes critically short causing genetic instability and thus cell cycle arrest. At this point, if telomeres do not become longer the cell will die. Telomeres are elongated only by telomerase, an enzyme that after development is active in just a handful of cell types in a mature organism. Such cells are lymphocytes.The aim of this study was to investigate the activity of telomerase protein in lymphocytes from chronic kidney disease and hemodialysis patients and to try and uncover if there is a relationship between this activity and the concentration of certain inflammation markers in these patients. These markers were TNF-a, CRP, IL-10 and IL-6. In addition the expression of telomerase catalytic subunit gene (hTERT) was measured in both patients groups and in healthy controls while the expression of tumor suppressor genes p53 and RB was also investigated. Enzymatic activity and gene expression were measured immediately after cell isolation and after the completion of 4 distinct cell cultures (with the addition of LPS or CRP or LPS-LXA4 and without the addition of any specific factor) while inflammation markers were calculated in the blood serum of patients and controls.Renal failure is characterized by a gradual decline in GFR and cause a variety of symptoms from almost every system of the particular organism. In recent years chronic inflammation has emerged as a very crucial mortality and morbidity factor in these patients. The results of this study show that a decrease in telomerase activity is observed in renal failure a fact that is associated with high rates of inflammation markers. In the meantime, even when culture conditions are changed lymphocytes from renal patients are less easy to be stimulated in vitro to divide when compared to healthy individuals. If inflammation is the cause for the decline in telomerase activity remains to be investigated.Τα τελομερή αποτελούν ιδιαίτερες νουκλεοπρωτεϊνικές δομές στα άκρα των ευθύγραμμων χρωμοσωμάτων τα οποία μειώνονται σε μήκος μετά από κάθε κυτταρική διαίρεση. Μετά από ορισμένο αριθμό διαιρέσεων, τα τελομερή βρίσκονται πλέον σε κρίσιμα μικρό μήκος και ως αποτέλεσμα προκαλείται γενετική αστάθεια η οποία έχει ως επακόλουθο την παύση του κυτταρικού κύκλου. Στο σημείο αυτό, αν τα τελομερή δεν επιμηκυνθούν, το κύτταρο θα πεθάνει. Τα τελομερή επιμηκύνονται μόνο από την τελομεράση, ένα ένζυμο που μετά την ανάπτυξη βρίσκεται ενεργοποιημένο σε ελάχιστους τύπους κυττάρων ενός ώριμου οργανισμού, όπως για παράδειγμα είναι τα λεμφοκύτταρα.Σκοπός αυτής της εργασίας ήταν να διερευνηθεί η ενεργότητα της τελομεράσης σε λεμφοκύτταρα ασθενών με χρόνια νεφρική ανεπάρκεια, αιμοκαθαρόμενους ή μη καθώς και να βρεθεί, αν υπάρχει, κάποια συσχέτιση μεταξύ αυτής της ενζυμικής δράσης και της συγκέντρωσης στο αίμα συγκεκριμένων παραγόντων φλεγμονής δηλαδή του TNF-a, της CRP, της IL-10 και της IL-6. Ταυτόχρονα στις δύο ομάδες ασθενών (αιμοκαθαρόμενοι και νεφροπαθείς μη αιμοκαθαρόμενοι) αλλά και στους φυσιολογικούς μάρτυρες, μελετήθηκε η έκφραση του γονιδίου της καταλυτικής υπομονάδας της τελομεράσης hTERT, καθώς και των ογκοκατασταλτικών γονιδίων p53 και RB. Η ενζυμική ενεργότητα και η γονιδιακή έκφραση μετρήθηκαν τόσο αμέσως μετά την απομόνωση των λεμφοκυττάρων όσο και μετά από 4 συγκεκριμένες κυτταροκαλλιέργειες (με προσθήκη LPS ή CRP ή LPS-LXA4, και χωρίς την προσθήκη κάποιου παράγοντα) ενώ οι παράγοντες φλεγμονής υπολογίστηκαν στον ορό αίματος ασθενών και μαρτύρων.Η χρόνια νεφρική ανεπάρκεια χαρακτηρίζεται από προοδευτική μείωση του ρυθμού σπειραματικής διήθησης και προκαλεί συμπτώματα από όλα σχεδόν τα συστήματα ενός οργανισμού. Σχετικά πρόσφατα αποκαλύφθηκε πως η χρόνια φλεγμονή αποτελεί έναν σημαντικό παράγοντα νοσηρότητας και θνητότητας στους ασθενείς αυτούς. Τα αποτελέσματα της έρευνας έδειξαν πως στη χρόνια νεφρική ανεπάρκεια προκαλείται μείωση της δραστηριότητας της τελομεράσης, γεγονός που συνδυάζεται με υψηλούς τίτλους παραγόντων φλεγμονής. Ταυτόχρονα παρά τις διάφορες αλλαγές στις συνθήκες καλλιέργειας τα κύτταρα των ασθενών ενεργοποιούνται in vitro δυσκολότερα ώστε να διαιρεθούν συγκριτικά με τους φυσιολογικούς μάρτυρες. Αν η φλεγμονή είναι αυτή που προκαλεί τη μειωμένη ενζυμική δραστικότητα είναι ακόμη προς διερεύνηση

The Telomere/Telomerase System in Chronic Inflammatory Diseases. Cause or Effect?

Telomeres are specialized nucleoprotein structures located at the end of linear chromosomes and telomerase is the enzyme responsible for telomere elongation. Telomerase activity is a key component of many cancer cells responsible for rapid cell division but it has also been found by many laboratories around the world that telomere/telomerase biology is dysfunctional in many other chronic conditions as well. These conditions are characterized by chronic inflammation, a situation mostly overlooked by physicians regarding patient treatment. Among others, these conditions include diabetes, renal failure, chronic obstructive pulmonary disease, etc. Since researchers have in many cases identified the association between telomerase and inflammation but there are still many missing links regarding this correlation, the latest findings about this phenomenon will be discussed by reviewing the literature. Our focus will be describing telomere/telomerase status in chronic diseases under the prism of inflammation, reporting molecular findings where available and proposing possible future approaches

The Telomere/Telomerase System in Chronic Inflammatory Diseases. Cause or Effect?

Telomeres are specialized nucleoprotein structures located at the end of linear chromosomes and telomerase is the enzyme responsible for telomere elongation. Telomerase activity is a key component of many cancer cells responsible for rapid cell division but it has also been found by many laboratories around the world that telomere/telomerase biology is dysfunctional in many other chronic conditions as well. These conditions are characterized by chronic inflammation, a situation mostly overlooked by physicians regarding patient treatment. Among others, these conditions include diabetes, renal failure, chronic obstructive pulmonary disease, etc. Since researchers have in many cases identified the association between telomerase and inflammation but there are still many missing links regarding this correlation, the latest findings about this phenomenon will be discussed by reviewing the literature. Our focus will be describing telomere/telomerase status in chronic diseases under the prism of inflammation, reporting molecular findings where available and proposing possible future approaches

Serum oxidized low-density lipoprotein is inversely correlated to telomerase activity in peripheral blood mononuclear cells of haemodialysis patients

Background. Telomerase preserves telomeres’ function and structure preventing cellular senescence. Its activity is reduced in peripheral blood mononuclear cells (PBMC) of haemodialysis (HD) patients. The purpose of this study is to investigate the potential correlation between increased oxidative stress/inflammation and telomerase activity in PBMC of HD patients. Methods: Telomerase activity was measured by PCR-ELISA in PBMC isolated from a group of 42 HD patients and 39 subjects with estimated glomerular filtration rate >= 80 mL/min (control group). Serum oxidized low-density lipoprotein (ox-LDL), tumour necrosis factor-alpha (TNF-alpha) and interleukin-10 (IL-10) were also measured in both groups by ELISA. Results: Ox-LDL was negatively correlated to percentage telomerase activity in PBMC (r = -0.506, P = 0.000 in the whole group of 81 HD and normal subjects and r = -0.559, P < 0.001 in HD patients). TNF was also inversely associated with percentage telomerase activity in the whole group studied (r= -0.492, P= 0.000) while IL-10 was not. In stepwise multiple linear regression, taking into consideration the most important characteristics of the HD patients and control group, the only significant predictors for percentage telomerase activity in PBMC were ox-LDL and TNF (beta = -0.421, t= -4.083, P= 0.000 and beta= -0.381, t= -3.691, P= 0.000, respectively) while examining separately HD patients, the predictors for the same parameter were ox-LDL and HD duration (beta = -0.671, t = -4.709, P = 0.000 and beta= -0.349, t = -2.447, P = 0.023, respectively). Conclusion: Ox-LDL serum level is inversely correlated to telomerase activity in PBMC of HD patients. Our study proposes a new consequence of increased oxidative stress in HD patients: the premature cellular senescence potentially related to atherosclerosis through LDL oxidation