Intact type 1 immunity and immune-associated coagulative responses in mice lacking IFNγ-inducible fibrinogen-like protein 2

Abstract

Fibrinogen-like protein 2 (Fgl2, fibroleukin) is a leukocyte product that exhibits significant homology to secreted proteins of diverse function, including growth factors, lectins, and components of extracellular matrix. Prior studies found that Fgl2 is IFN␥-inducible, possesses direct coagulant activity, and inhibits T cell proliferation and dendritic cell maturation in vitro. Here, we demonstrate that Fgl2 expression is up-regulated during type 1 immunity in vivo and establish that such up-regulation is IFN␥-, signal transducer and activation of transcription protein 1-, and IFN response factor 1-dependent. To investigate functional roles for Fgl2 during type 1 immunity, we generated Fgl2-deficient mice. Those animals are born at predicted Mendelian frequencies, appear overtly healthy, and contain normal numbers and frequencies of lymphoid cells. Although Fgl2 is IFN␥-inducible and putatively regulates T cell activation͞proliferation, we demonstrate that Fgl2-deficient and control mice exhibit similar degrees of T cell expansion, immunopathology, and͞or pathogen burdens during protozoan (Toxoplasma gondii), bacterial (Yersinia enterocolitica, Listeria monocytogenes, and Mycobacterium tuberculosis), and viral (murine ␥-herpesvirus-68 and Sendai) infections. Fgl2-deficient mice also reject allografts with similar kinetics as control mice. Moreover, despite prior reports that Fgl2 functions as a procoagulant enzyme, we demonstrate that Fgl2-deficient and control mice produce similar levels of fibrin, a product of the coagulation cascade, during T. gondii infection and allograft rejection. Together, our findings suggest that Fgl2, although highly conserved and IFN␥-inducible, is not a critical mediator of either type 1 immunity or immuneassociated coagulant activity.

Role of Fibrinogen-Like Protein 2 Prothrombinase/Fibroleukin in Experimental and Human Allograft Rejection

“…Collectively, these studies support the hypothesis that (donor) endothelial cell production of mfgl2, rather than an immune-activated infiltrating leukocyte population, accounts for the fibrin deposition in allorejection (6). These data are further supported by our recent studies in xenotransplantation in which fibrin deposition associated with xenograft rejection was largely intravascular rather than associated with infiltrating inflammatory cells (21).…”

“…The importance of fgl2 to allograft rejection is supported first by the observation that expression of fgl2 correlates with rejection (6) and also by the fact that administration of neutralizing Ab to fgl2 diminished the pathological injury and improved graft survival in a similar fashion to that previously reported in murine hepatitis infection (20).…”

“…Recent studies from Hancock et al (6) have also examined the relevance of mfgl2 to fibrin deposition in allorejection. Their studies, similar to ours, showed that mfgl2 Ϫ/Ϫ recipient mice rejected FIGURE 6.…”

“…Previously, Hancock et al (5) have suggested that mfgl2 expression is correlated with allograft rejection, and strategies known to prevent allorejection including infusion of anti-CD154 prevent expression of mfgl2. However, this group recently also suggested that disruption of mfgl2 did not alter type 1 immunity or fibrin deposition associated with allograft rejection (6).…”

Global analysis of gene expression inXenopushindlimbs during stage‐dependent complete and incomplete regeneration

“…FGL2 is expressed in several subsets of T-lymphocytes, including gut mucosal lymphocytes (Ruegg and Pytela, 1995) as well as activated hepatic endothelial cells and macrophages (Marsden et al, 2003). FGL2 is induced in type 1 lymphocytes by IFN signaling pathways, including irf1 (Hancock et al, 2004), which we found up-regulated in our array screen (see Supplementary Materials). Conflicting data from FGL2-deficient mice experiments show that FGL2 may or may not contribute to immunologically mediated thrombosis (Marsden et al, 2003;Hancock et al, 2004).…”