The Trypanosoma cruzi trans-Sialidase, through Its Cooh-Terminal Tandem Repeat, Upregulates Interleukin 6 Secretion in Normal Human Intestinal Microvascular Endothelial Cells and Peripheral Blood Mononuclear Cells

doi:10.1084/jem.190.12.1825

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© The Rockefeller University Press, 0022-1007/1999/12/1825/ $5.00
The Journal of Experimental Medicine, Volume 190, Number 12, December 20, 1999 1825-1836

Original Article

The Trypanosoma cruzi trans-Sialidase, through Its Cooh-Terminal Tandem Repeat, Upregulates Interleukin 6 Secretion in Normal Human Intestinal Microvascular Endothelial Cells and Peripheral Blood Mononuclear Cells

Emma Saavedra^a, Macario Herrera^a, Wenda Gao^a, Haruki Uemura^b, and Miercio A. Pereira^a

^a Parasitology Research Center, Department of Pathology, Tufts University School of Medicine, Boston, Massachusetts 02111
^b Institute of Tropical Medicine, Nagasaki University, Nagasaki 852-8523, Japan
Department of Pathology, Parasitology Research Center, Tufts University School of Medicine, 136 Harrison Ave., Boston, MA 02111.617-636-6849617-636-2933

maperrin{at}yahoo.com

The Trypanosoma cruzi trans-sialidase can sensitize mice tobecome highly susceptible to T. cruzi invasion, through mechanismsthat remain unknown. In pursuing this observation, we foundthat purified trans-sialidase induces the selective releaseof biologically active interleukin (IL)-6 in naive human intestinalmicrovascular endothelial cells (HIMECs), peripheral blood mononuclearcells (PBMCs), and bladder carcinoma cells. The trans-sialidaseaction was independent of its catalytic activity, as demonstratedwith a genetically engineered trans-sialidase mutant, an enzymaticallyactive polypeptide, and cocultures of PBMCs with epimastigotesand trypomastigotes. Instead, the trans-sialidase action wasreproduced with a recombinant COOH-terminal tandem repeat andwith synthetic peptides modeled on the tandem repeat. Most interesting,HIMECs infected with a trypomastigote population expressingtrans-sialidase effectively released IL-6, but did not uponinfection with the counterpart trypomastigote population expressinglow trans-sialidase levels. IL-6 is a key factor in the regulationand symptom formation of infection caused by several types ofviruses, such as HIV and influenza A virus. However, the functionof IL-6 in protozoan and other parasitic diseases remains unclear.The unique findings presented here suggest that trans-sialidaseis a major inducer of IL-6 secretion in T. cruzi infection,independently of immune cell activation. Such IL-6 secretionmight underlie some features of Chagas's disease, such as pyrexia,neuroprotection, and fibrosis, and might result in the underminingof normal acquired immunity against T. cruzi.

Key Words: interleukin 6 • trans-sialidase • cytokines • Trypanosoma cruzi • endothelial cells

Abbreviations used in this paper: CD, catalytic domain of TS;CM, conditioned medium; GAPDH, glyceraldehyde 3-phosphate dehydrogenase;HIMEC, human intestinal microvascular endothelial cell; HUVEC,human umbilical vein endothelial cell; NTA, nitrilotriaceticacid; PN-1, penetrin; RANTES, regulated upon activation, T cellexpressed and secreted; TS, trans-sialidase; TR, tandem repeat;TS/CM, TS-stimulated CM; VCNA, Vibrio cholera neuraminidase.

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