MECHANISMS OF NOVEL ANTI-INFLAMMATORY ACTIONS OF SLPI

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DESCRIPTION (provided by applicant): Secretory leukocyte protease inhibitor (SLPI) and proepithelin (PEPI) were originally discovered as two unrelated secreted products of epithelial cells. SLPI is a small 12-kDa leukocyte protease inhibitor, while PEPI is best known as the precursor for epithelins (EPIs), a group of 6-kDa peptides with unknown functions that are found in diverse tissues and body fluids. Leukocytes, especially macrophages, are also rich sources of SLPI and PEPI. Expression of both proteins is upregulated in macrophages by microbial products such as lipopolysaccharide (LPS). We have identified PEPI as a SLPI interacting protein. We also discovered that PEPI and EPIs exert opposing biological activities. EPIs promote whereas PEPI downregulates inflammatory reactions. Binding of PEPI by SLPI prevents its conversion to EPIs. Both SLPI and PEPI block TNF-triggered neutrophil activation. SLPI also suppresses the macrophage response to LPS. Thus, SLPI and PEPI appear to be a pair of host-derived anti-inflammatory mediators that serve to prevent excess innate immune responses. The underlying mechanisms for the anti-inflammatory actions of SLPI and PEPI are poorly understood. The goal of this project is to further explore the mechanisms of the novel anti-inflammatory actions of SLPI and PEPI. We will focus on: (1) characterizing the role of PEPI/EPIs in the inflammatory responses of leukocytes; (2) understanding the molecular basis by which SLPI and PEPI affect macrophage function; and (3) testing the role of SLPI and PEPI in three in vivo inflammation models (cutaneous wounding, smoke-induced emphysema and septic shock induced by cecal-ligation and puncture) using PEPI and SLPI knock out mice and SLPI transgenic mice. Elucidating how SLPI and PEPI interfere with specific steps in LPS signaling may contribute important insights to the pathophysiology of inflammation-related diseases including septic shock and to the development of novel therapeutic strategies.