Molecular Regulation of Inflammatory Cytokine Production in Macrophages

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Background: An important function of the immune system is to initiate inflammatory response that is required to control insults and initiate tissue repair. The inflammatory process is normally self-limiting and regulated in order to avoid collateral tissue-damage. A dysregulation of inflammation results in excessive and persistent inflammation, which is characterized by elevated expression of proinflammatory cytokines. Myeloid immune cells (particularly macrophages and neutrophils) play important roles in inflammation via their production of inflammatory mediators including cytokines. The molecular mechanisms controlling inflammation have not been fully delineated.Recently, we showed that Diminazene aceturate (Berenil, which is an aromatic diamidine), inhibits IL-1, IL-6, IL-12 and TNF production by macrophages in vivo and in vitro following stimulation with Trypanosoma congolense, lipopolysaccharide (LPS) and CpG. We recently in preliminary studies validated these findings using newer and safer diamidine compounds. This global suppressive effect was due to downregulation of phosphorylation of mitogen-activated protein kinases (MAPKs, including ERK, p38 and JNK), signal transducer and activator of transcription (STAT) proteins (STAT1 and STAT3) and NFB p65 subunit, which are key signaling molecules and transcription factors involved in the production of proinflammatory cytokines. Berenil also increases neutrophil numbers in lungs, blood and peritoneal lavage fluids following LPS challenge. The molecular mechanisms through which Berenil mediates increased neutrophil survival and/or number is unknown. The overarching goal of the current renewal application is to identify trypanosome molecule(s) that induce inflammatory cytokines and determine molecular mechanisms by which Berenil regulates inflammatory cytokine production by macrophages and neutrophils in vitro and in vivo. The objectives are: (i) to dissect the molecules and mechanisms through trypanosomes induce proinflammatory cytokines (Project 1), (ii) determine molecular mechanisms through which Berenil suppresses proinflammatory cytokine production in macrophages (Project 2) and (iii) determine whether Berenil increases neutrophil survival, recruitment and/or mobilization from the bone marrow by assessing markers of apoptosis in neutrophils from various tissue (Project 3). Significance: The proposed studies will establish the mechanistic processes involved in the anti-inflammatory properties of Berenil. The long-term vision is to have a broad and in-depth understanding of mechanisms that regulate inflammatory responses, which may reveal novel ways of targeting inflammatory conditions. The novelty of the research project and the cutting edge technologies involved will continue to create a rich environment for the training of HQP (2-3 graduate and 5 undergraduate students).