Modulation of acute inflammation by targeting glycosaminoglycan-cytokine interactions.
Glycosaminoglycans (GAGs) located on cellular membranes and the extracellular matrix (ECM) are able to interact with chemokines and pro-inflammatory cytokines, leading to local cytokine/chemokine accumulation. The tissue-bound cytokines/chemokines function in promoting leukocyte migration and activation, contributing to local inflammation. Hence, targeting of GAG-cytokine interactions may provide an avenue for the attenuation of inflammatory responses. A cationic peptide (MC2) derived from the heparin-binding sequence of mouse IFN-gamma was previously shown by our laboratory to delay allograft rejection in an animal model. In order to further investigate potential anti-inflammatory properties of the MC2 peptide, we have studied its activity in an acute peritoneal inflammation model. Groups of C57Bl/6 mice were injected intraperitoneally with either ConA or thioglycollate and treated with saline (control), the MC2 peptide or two control cationic peptides, poly-l-lysine (PLL) and poly-l-arginine (PLA). Treatment with the MC2 peptide, but not PLA or PLL, resulted in statistically significant reductions in total cell numbers, concentration of total proteins and concentrations of pro-inflammatory cytokines (TNFalpha, IL-6 or IL-1 beta) in peritoneal lavage fluids, without alterations to the qualitative cellular composition of the exudate. These results suggest that targeting GAG-cytokine interaction is a viable approach to reduce inflammation.
Cripps
James G
JG
Department of Pathology and Laboratory Medicine, School of Medicine, University of Louisville, Louisville, KY 40292, USA.
Crespo
Fabián A
FA
Romanovskis
Peteris
P
Spatola
Arno F
AF
Fernández-Botrán
Rafael
R
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001202:Ascitic Fluid / Q000166:cytology / Q000378:metabolism; D002478:Cells, Cultured; D003208:Concanavalin A; D016207:Cytokines / Q000378:metabolism / Q000502:physiology*; D005260:Female; D006025:Glycosaminoglycans / Q000378:metabolism / Q000502:physiology*; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010446:Peptide Fragments / Q000494:pharmacology*; D011506:Proteins / Q000494:pharmacology*; D013864:Thioglycolates
D000893:Anti-Inflammatory Agents; D016207:Cytokines; D006025:Glycosaminoglycans; C506054:MC2 peptide; C454979:MC2 protein, mouse; D010446:Peptide Fragments; D011506:Proteins; D013864:Thioglycolates; D003208:Concanavalin A; D007371:Interferon-gamma