Regulation of macrophage alternative activation by eicosanoids

• Antragsteller: Dr. Zbigniew Jan Zaslona
• Fachliche Zuordnung: Pneumologie,Thoraxchirurgie
• Förderung: Förderung von 2010 bis 2011
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 183569788

Macrophages are innate immune cells that play a pivotal role in defense against infection, coordination of inflammatory responses, and tissue homeostasis. Macrophages can be classically activated by IFN- to direct a pro-inflammatory cascade directed against intracellular pathogens, or alternatively activated by IL- 4 and IL-13 to combat parasitic infections. Prostaglandins and leukotrienes are the best-studied lipid mediators derived from arachidonic acid (collectively termed “eicosanoids“), and are implicated in diverse biological functions, including inflammation. Prostaglandins are generated by cyclooxygenase (COX) isozymes while leukotrienes are synthesized by 5- lipoxygenase (5-LO). Prostaglandin E2 (PGE2) and leukotriene B4 (LTB4) are well-established modulators of macrophage immune responses and cytokine and chemokine expression, often acting in opposition to each other. Virtually nothing is known about the influence of eicosanoids on macrophage alternative activation. Here we propose that the balance of PGE2 and LTB4 synthesis and actions via their respective G protein-coupled receptors EP2 and BLT1 is a critical determinant of macrophage alternative activation. Actions of these two eicosanoids reflect their opposing effects on the generation of cAMP, which through the effectors protein kinase A (PKA) and exchange protein activated directly by cAMP (Epac), may control macrophage differentiation. The influence of eicosanoids and cAMP signaling on macrophage alternative activation will be investigated in vitro and in a mouse model of allergic asthma.

• DFG-Verfahren: Forschungsstipendien
• Internationaler Bezug: USA
• Gastgeber: Professor Marc L. Peters-Golden