? 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. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM061710-07
Application #
7068658
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Dunsmore, Sarah
Project Start
2000-06-01
Project End
2008-05-31
Budget Start
2006-06-01
Budget End
2007-05-31
Support Year
7
Fiscal Year
2006
Total Cost
$347,790
Indirect Cost
Name
Weill Medical College of Cornell University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
060217502
City
New York
State
NY
Country
United States
Zip Code
10065
Marino, Rafael; Thuraisingam, Thusanth; Camateros, Pierre et al. (2011) Secretory leukocyte protease inhibitor plays an important role in the regulation of allergic asthma in mice. J Immunol 186:4433-42
He, Guoan; Ma, Yao; Chou, Szu-Yi et al. (2011) Role of CLIC4 in the host innate responses to bacterial lipopolysaccharide. Eur J Immunol 41:1221-30
Tang, Wei; Lu, Yi; Tian, Qing-Yun et al. (2011) The growth factor progranulin binds to TNF receptors and is therapeutic against inflammatory arthritis in mice. Science 332:478-84
Yin, Fangfang; Banerjee, Rebecca; Thomas, Bobby et al. (2010) Exaggerated inflammation, impaired host defense, and neuropathology in progranulin-deficient mice. J Exp Med 207:117-28
Ghasemlou, Nader; Bouhy, Delphine; Yang, Jingxuan et al. (2010) Beneficial effects of secretory leukocyte protease inhibitor after spinal cord injury. Brain 133:126-38
Yin, Fangfang; Dumont, Magali; Banerjee, Rebecca et al. (2010) Behavioral deficits and progressive neuropathology in progranulin-deficient mice: a mouse model of frontotemporal dementia. FASEB J 24:4639-47
Kim, Younghwa; Zhou, Ping; Qian, Liping et al. (2007) MyD88-5 links mitochondria, microtubules, and JNK3 in neurons and regulates neuronal survival. J Exp Med 204:2063-74
Cohn, Ellen F; Nathan, Carl; Radzioch, Danuta et al. (2006) Abrupt expression of TLR4 in TLR4-deficient macrophages imposes a selective disadvantage: genetic evidence for TLR4-dependent responses to endogenous, nonmicrobial stimuli. J Immunol 176:1185-94
Wang, Ni; Thuraisingam, Thusanth; Fallavollita, Lucia et al. (2006) The secretory leukocyte protease inhibitor is a type 1 insulin-like growth factor receptor-regulated protein that protects against liver metastasis by attenuating the host proinflammatory response. Cancer Res 66:3062-70
Sun, Dongxu; Ding, Aihao (2006) MyD88-mediated stabilization of interferon-gamma-induced cytokine and chemokine mRNA. Nat Immunol 7:375-81

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