Document Detail

Modulation of inflammation by slit protein in vivo in experimental crescentic glomerulonephritis.
MedLine Citation:
PMID:  15215188     Owner:  NLM     Status:  MEDLINE    
A basic conservation of cell migration guidance mechanisms in the nervous and immune systems was proposed when Slit, known for its role in axon guidance, was found to inhibit chemokine-induced leukocyte chemotaxis in vitro. These studies examined the role of Slit2 in modulating inflammation in vivo. In a rat model of glomerulonephritis, endogenous glomerular Slit2 expression fell after disease induction, and its inhibition during the early disease period accelerated inflammation. Ex vivo glomerular leukocytes showed decreased chemokine and chemoattractant-induced chemotaxis in response to Slit2, suggesting an anti-inflammatory role for glomerular Slit2. In contrast to the effect of inhibition, glomerulonephritis was ameliorated by systemic Slit2 administration. Slit2 treatment improved disease histologically and also improved renal function when given early in the disease course. Leukocytes harvested from rats receiving Slit2 showed decreased monocyte chemoattractant protein-1 (MCP)-1-mediated migration, consistent with a peripheral Slit2 effect. In keeping with this functional alteration, Slit2-mediated inhibition of RAW264.7 cell chemotaxis was associated with decreased levels of active cdc42 and Rac1, implicating GTPases in leukocyte Slit2 signaling. These findings suggest a role for endogenous Slit2 in the inhibition of chemoattractant-mediated signals, demonstrate a potentially important anti-inflammatory effect for Slit2 in vivo, and provide further evidence for conserved mechanisms guiding the process of migration in distinct cell types.
John Kanellis; Gabriela E Garcia; Ping Li; Gustavo Parra; Curtis B Wilson; Yi Rao; Suhua Han; C Wayne Smith; Richard J Johnson; Jane Y Wu; Lili Feng
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  The American journal of pathology     Volume:  165     ISSN:  0002-9440     ISO Abbreviation:  Am. J. Pathol.     Publication Date:  2004 Jul 
Date Detail:
Created Date:  2004-06-24     Completed Date:  2004-09-03     Revised Date:  2014-09-16    
Medline Journal Info:
Nlm Unique ID:  0370502     Medline TA:  Am J Pathol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  341-52     Citation Subset:  AIM; IM    
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MeSH Terms
Antigens, CD / metabolism
Blotting, Western
Cell Line
Chemokine CCL2 / metabolism
Chemotaxis, Leukocyte / drug effects
Disease Models, Animal
Flow Cytometry
Gene Expression Regulation / drug effects
Glomerulonephritis / etiology,  metabolism*,  pathology,  physiopathology
Inflammation / drug therapy*
Intercellular Signaling Peptides and Proteins
Leukocytes, Mononuclear / drug effects
Nerve Tissue Proteins / administration & dosage*,  metabolism*
RNA, Messenger / metabolism
Rats, Inbred WKY
Recombinant Proteins / administration & dosage*,  metabolism*
Reverse Transcriptase Polymerase Chain Reaction
rac1 GTP-Binding Protein / metabolism
Grant Support
DK 55730-03/DK/NIDDK NIH HHS; P50 DK 064233-01/DK/NIDDK NIH HHS; R01 CA114197/CA/NCI NIH HHS; R01 CA114197-01A2/CA/NCI NIH HHS; R01 EY014576/EY/NEI NIH HHS; R01 EY014576-03/EY/NEI NIH HHS; R01 GM070967/GM/NIGMS NIH HHS; R01 GM070967-02/GM/NIGMS NIH HHS
Reg. No./Substance:
0/Antigens, CD; 0/Chemokine CCL2; 0/Intercellular Signaling Peptides and Proteins; 0/Nerve Tissue Proteins; 0/RNA, Messenger; 0/Recombinant Proteins; 0/Slit homolog 2 protein; EC GTP-Binding Protein

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