Ours was the original report of the cloning of the CCAAT/Enhancer Binding Protein (C/EBP)b . We have established that site-specific phosphorylations of C/EBPb are critical modulators of gene expression, cell- cycle progression, apoptotic programs, immune modulation and tissue inflammation and repair. C/EBPb-phosphorylation mutant models of human diseases were extensively utilized by us to make these discoveries. Unexpectectly, we have recently determined that phosphorylation of C/EBPb-Thr217 on its transactivation domain by ribosomal S6-kinase (RSK)-2 plays a major role in inducing liver macrophage M1 ('classical', 'pro-inflammatory') activity. This is the first specific phosphorylation known to modulate the macrophage M1 to M2 switch. Identification and characterization of the M1/M2 paradigm may provide new insights into liver macrophage and stellate cell biology as well as potential therapeutic strategies for the prevention and treatment of liver injury. It provides an opportunity to control liver inflammation and injury in patients with acute and chronic liver diseases as well as potential therapeutic strategies for the prevention and treatment of liver inflammation and injury. This novel modulation of liver macrophage M1 pro-inflammatory activity is essential in understanding liver inflammation and injury and its critical role in the activation of stellate cells. SPECIFIC OBJECTIVES This proposal will study the mechanisms by which phosphorylation of C/EBPb-Thr217 modulates the 'inflammatory'M1 macrophage response, thereby, inducing liver inflammation and increasing liver injury.
Specific Aim 1. The phosphorylation state of C/EBPb-Thr217 modulates the macrophage M1/M2 phenotype Specific Aim 2. The effects of M1 and M2 liver macrophages on stellate cells activation.
Specific Aim 3. The effects of RSK-inhibitory peptides on the macrophage M1/M2 phenotype.
Specific Aim 4. Optimization of RSK-inhibitory peptides for the prevention and treatment of liver inflammation and injury.
PROJECT NARRATIVE In acute and chronic liver diseases, through inflammation and injury induce damage to the liver, resulting in liver failure. Excessive liver damage accounts for the significant complications and mortality among the VA population with acute and chronic liver diseases. The medical and financial burden of liver diseases to the Veteran's Administration is substantial, as it is associated with Hepatitis B and C, rejection of a transplanted liver, auto-immune hepatitis, fatty liver of obesity and diabetes and alcoholism. Additional knowledge gained by this work will add to the understanding of liver inflammation and injury may lead to better treatments. Development of effective treatments for liver inflammation and injury may also facilitate future treatments for lung and kidney inflammation and injury.