Ccr2 regulates the level of MCP-1/CCL2 in vitro and at inflammatory sites and controls T cell activation in response to alloantigen.
CCR2, and its principle ligand MCP-1/CCL2, have been well documented for their ability to induce monocyte infiltration and promote the pathogenesis of rheumatoid arthritis and atherosclerosis. In order to assess additional roles for CCR2, we inserted allogeneic implants into CCR2-/- and MCP-1-/- mice and characterized T cell responses and the regulatory role of CCR2 on MCP-1 expression. The results demonstrate a marked decrease in lymphocyte infiltration in both CCR2-/- and MCP-1-/- animals. In contrast, IL-12 and CTL function were only suppressed in CCR2-/- animals. Further, whereas MCP-1 was only transiently elevated in the inflammatory fluid of WT animals, levels were sustained within the implants (5000pg/ml; >8 days) and serum (243pg/ml) of CCR2-/- mice. Higher levels of MCP-1 were also observed in the culture supernatants of CCR2-/- macrophages as compared to WT cells despite no difference in mRNA levels. Evidence that MCP-1 levels are regulated by receptor binding and internalization was suggested by its rapid decline when added to WT macrophages at 37 degrees C but not 4 degrees C. These studies indicate that CCR2 plays an important role in regulating T cell responses and controlling the level of MCP-1 at inflammatory sites.
Pfizer Global Research and Development, Department of Immunology, Groton, CT 06340, USA. Ronald_P_Gladue@Groton.Pfizer.com
L A
LA
Tylaska
L
L
Boring
W
W
Weng
R
R
Aiello
I F
IF
Charo
B J
BJ
Rollins
R P
RP
Gladue
D000818:Animals; D018932:Chemokine CCL2 / Q000096:biosynthesis*; D005838:Genotype; D007249:Inflammation; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000096:biosynthesis / Q000378:metabolism; D015847:Interleukin-4 / Q000096:biosynthesis; D007519:Isoantigens; D008213:Lymphocyte Activation; D008214:Lymphocytes / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000378:metabolism; D010641:Phenotype; D054390:Receptors, CCR2; D019707:Receptors, Chemokine / Q000096:biosynthesis* / Q000502:physiology*; D012260:Ribonucleases / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology*; D013696:Temperature; D013997:Time Factors
C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; D007519:Isoantigens; D054390:Receptors, CCR2; D019707:Receptors, Chemokine; D018664:Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma; D012260:Ribonucleases