Trypanosoma cruzi, the causative agent of Chagas disease, modulates interleukin-6-induced STAT3 phosphorylation via gp130 cleavage in different host cells.

PONCE NE, CARRERA SILVA EA, PELLEGRINI AV, CAZORLA SI, MALCHIODI EL, LIMA AP, GEA S, AOKI MP.

BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR BASIS OF DISEASE

ELSEVIER SCIENCE BV

Lugar: Amsterdam; Año: 2013 vol. 1832 p. 485 - 494

0925-4439

Interleukin-6 mediates host defense and cell survival mainly through theactivation of the transcription factor STAT3 via the glycoprotein gp130, a sharedsignal-transducing receptor for several IL-6-type cytokines. We have reportedthat the cardiotrophic parasite Trypanosoma cruzi protects murine cardiomyocytes from apoptosis. In agreement, an intense induction of the anti-apoptotic factorBcl-2 is found in cardiac fibers during the acute phase of infection,establishing a higher threshold against apoptosis. We report here that inactivecruzipain, the main cysteine protease secreted by the parasite, specificallytriggered TLR2 and the subsequent release of IL-6, which acted as an essentialanti-apoptotic factor for cardiomyocyte cultures. Although comparable IL-6 levelswere found under active cruzipain stimulation, starved cardiac cell monolayerscould not be rescued from apoptosis. Moreover, cardiomyocytes treated with activecruzipain completely abrogated the STAT3 phosphorylation and nucleartranslocation induced by recombinant IL-6. This inhibition was also observed onsplenocytes, but it was reverted when the enzyme was complexed with chagasin, aparasite cysteine protease inhibitor. Furthermore, the inhibition of IL-6-inducedp-STAT3 was evidenced in spleen cells stimulated with pre-activated supernatants derived from trypomastigotes. To account for these observations, we found thatcruzipain enzymatically cleaved recombinant gp130 ectodomain, and induced therelease of membrane-distal N-terminal domain of this receptor on human peripheralblood mononuclear cells. These results demonstrate, for the first time, that the parasite may modify the IL-6-induced response through the modulation of itscysteine protease activity, suggesting that specific inhibitors may help toimprove the immune cell activation and cardioprotective effects.