Open AccessTumor Necrosis Factor Alpha and Gamma Interferon, but Not Hemorrhage or Pathogen Burden, Dictate Levels of Protective Fibrin Deposition during Infection
Author(s) -
Isis K. Mullarky,
Frank M. Szaba,
Kiera N. Berggren,
Lawrence W. Kummer,
Lindsey B. Wilhelm,
Michelle A. Parent,
Lawrence L. Johnson,
Stephen T. Smiley
Publication year - 2006
Publication title -
infection and immunity
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.508
H-Index - 220
eISSN - 1070-6313
pISSN - 0019-9567
DOI - 10.1128/iai.74.2.1181-1188.2006
Subject(s) - fibrin , immunology , tumor necrosis factor alpha , biology , cytokine , coagulation , proinflammatory cytokine , tissue factor , immune system , inflammation , medicine
While coagulation often causes pathology during infectious disease, we recently demonstrated that fibrin, a product of the coagulation pathway, performs a critical protective function during acute toxoplasmosis (L. L. Johnson, K. N. Berggren, F. M. Szaba, W. Chen, and S. T. Smiley, J. Exp. Med.197: 801-806, 2003). Here, we investigate the mechanisms regulating the formation of this protective fibrin. Through comparisons ofToxoplasma -infected wild-type and cytokine-deficient mice we dissociate, for the first time, the relative fibrin-regulating capacities of pathogen products, host cytokines, and infection-stimulated hemorrhage. Remarkably, neither the pathogen burden nor hemorrhage is a primary regulator of fibrin levels. Rather, two type 1 cytokines exert dominant and counterregulatory roles: tumor necrosis factor alpha (TNF-α), acting via the type 1 TNF-α receptor, promotes fibrin deposition, while gamma interferon (IFN-γ), acting via STAT1 and IFN-γ receptors expressed on radioresistant cells, suppresses fibrin deposition. These findings have important clinical implications, as they establish that cytokines known to regulate pathological coagulation also dictate levels of protective fibrin deposition. We present a novel model depicting mechanisms by which the immune system can destroy infected tissue while independently restraining hemorrhage and promoting tissue repair through the deliberate deposition of protective fibrin.