Impairment of leukocyte trafficking in a murine pleuritis model by IL-4 and IL-10.
We have characterized leukocyte migration to the pleural cavity in a methylated-BSA (mBSA)-induced model of murine delayed-type hypersensitivity and evaluated the ability of IL-4 and IL-10 to modulate this response. Neutrophils, macrophages, T cells, and dendritic cells migrated to the pleural cavity in a time-dependent fashion following direct intrapleural antigen challenge, with neutrophils comprising the majority of exudate leukocytes in the cavity within the first 24 h and the number of mononuclear cells increasing at later times. Real-time quantitative PCR analysis of infiltrating leukocytes revealed a marked elevation of steady-state mRNA levels of IL-1beta and TNFalpha and the chemokines KC, MIP-2, CXCL9, CXCL10, CXCL11, CCL2, CCL3, and CCL4 at 6 h postchallenge, which diminished over time. In contrast, gammaIFN mRNA levels were maximal at 24 h and CCL5 expression was sustained throughout 72 h. ELISA analysis of pleural exudate fluid revealed significant elevations of KC and CCL2 protein levels at 6 h postantigen challenge and a peak increase in gammaIFN protein at 24 h, confirming our mRNA observations. Administration of recombinant murine IL-4 or IL-10 prior to challenge significantly blocked cell trafficking to the pleural cavity as well as peak levels of exudate gammaIFN, with IL-4 being more potent in impairing these responses. IL-4 administration also increased the proportion of naive T cells in the pleural cavity, as judged by CD62L and CD45RB expression. These results indicate that this in vivo model demonstrates a pattern of events associated with Th1-mediated leukocyte trafficking and underscore the potential utility of this in vivo model for evaluating therapeutic inhibitors of leukocyte trafficking.
Fine
Jay S
JS
Department of Immunology, Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA. jay.fine@spcorp.com
Rojas-Triana
Alberto
A
Jackson
James V
JV
Engstrom
Laura W
LW
Deno
Gregory S
GS
Lundell
Daniel J
DJ
Bober
Loretta A
LA
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000627:therapeutic use; D002465:Cell Movement / Q000276:immunology*; D004195:Disease Models, Animal; D005260:Female; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D016753:Interleukin-10 / Q000008:administration & dosage / Q000627:therapeutic use*; D015847:Interleukin-4 / Q000008:administration & dosage / Q000627:therapeutic use*; D007962:Leukocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D035422:Pleural Cavity / Q000276:immunology / Q000473:pathology; D010998:Pleurisy / Q000276:immunology* / Q000473:pathology* / Q000517:prevention & control; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000627:therapeutic use; D012710:Serum Albumin, Bovine / Q000008:administration & dosage / Q000276:immunology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D011994:Recombinant Proteins; C029180:methylated bovine serum albumin; D016753:Interleukin-10; D015847:Interleukin-4; D012710:Serum Albumin, Bovine; D007371:Interferon-gamma