Nuggets, Pearls, and Vignettes of Master Heart Failure Clinicians

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73696/1/j.1527-5299.2001.00307.x.pd

Alloimmune induction of endothelial cell-derived interferon-gamma-inducible chemokines

BACKGROUND: The interaction between host lymphocytes and endothelial cells on the transplanted organ is believed to play an important role in acute and chronic graft rejection. Trafficking and recruitment of lymphocytes to the site of inflammation is known to be controlled by several cytokines and chemokines. It is unclear whether endothelial cells themselves can be a source of inflammatory chemoattractant molecules on alloimmune induction. METHODS: Using a semiquantitative polymerase chain reaction method, the authors analyzed the expression of chemokine mRNA coding for interferon (IFN)-gamma-induced protein 10 (IP-10) and monokine induced by IFN-gamma (Mig) in a pool of human aortic endothelial cells. Both of these chemokines are known to be induced by IFN-gamma. Endothelial cell-derived chemokine mRNA was assayed at rest, after IFN-gamma activation, and after co-culture with allogeneic peripheral blood mononuclear cells (PBMC) from normal blood donors with and without a monoclonal antibody to IFN-gamma. Finally, protein release into the media was assayed using an enzyme-linked immunosorbent assay to IP-10. RESULTS: Mig and IP-10 were expressed in human endothelial cells both after IFN-gamma treatment and after PBMC co-culture. Furthermore, the expression of both of these endothelial cell-derived chemokines was dependent on IFN-gamma because PBMC-induced expression was blocked with anti-IFN-gamma. IP-10 levels in the endothelial cell supernatant increased from a baseline of 13.4+/-10.8 pg/mL to 299.5+/-13.4 pg/mL (P CONCLUSIONS: Vascular endothelial cells are capable of producing inflammatory chemokines when activated and potentially serve to amplify the allogeneic response

Activation of NF-κB by Double-Stranded RNA (dsRNA) in the Absence of Protein Kinase R and RNase L Demonstrates the Existence of Two Separate dsRNA-Triggered Antiviral Programs

Double-stranded RNA (dsRNA) of viral origin triggers two programs of the innate immunity in virus-infected cells. One is intended to decrease the rate of host cell protein synthesis and thus to prevent viral replication. This program is mediated by protein kinase R (PKR) and by RNase L and contributes, eventually, to the self-elimination of the infected cell via apoptosis. The second program is responsible for the production of antiviral (type I) interferons and other alarmone cytokines and serves the purpose of preparing naive cells for the viral invasion. This second program requires the survival of the infected cell and depends on the expression of antiapoptotic genes through the activation of the NF-κB transcription factor. The second program therefore relies on ongoing transcription and translation. It has been proposed that PKR plays an essential role in the activation of NF-κB by dsRNA. Here we present evidence that the dsRNA-induced NF-κB activity and the expression of beta interferon and inflammatory cytokines do not require either PKR or RNase L. Our results indicate, therefore, that the two dsRNA-activated programs are separate and can function independently of each other