However, regarding the comparable bone loss RWJ 64809 p38 MAPK inhibitor levels presented by both groups, it is possible that the similar levels of RANKL in the tissues are responsible for the equivalent bone resorption degree. Interestingly, the levels of IL-17A and IL-4, theoretically products of Th17- and Th2- polarized lymphocytes, were also reduced by the 5 mg met- RANTES dose. Since Th17 and Th2 helper subsets specifically migrate using the chemokine receptors CCR6 and CCR4/CCR8 , not targeted by met-RANTES, our data demonstrate that the higher dose result in a broader and probably unspecific modulation of host response, not observed with the 0.5 mg dose. One possible explanation for such phenomenon is that the high VE-822 in vivo met-RANTES doses could interfere indirectly in the cell migration mediated by other receptor than CCR1 and CCR5. In fact, our data demonstrate a reduction in the number of CD19 and Gr1 positive cells, presumably B cells and neutrophils respectively, cells which normally do not present CCR1 and CCR5 receptors, by 5 mg dose of met-RANTES. Chemokine receptor blockade by met-RANTES limits the endothelial cell-leukocyte interaction, which consequently can limit the migration process even if mediated by non-blocked receptors. Also, the continuous administration of a high amount of met-RANTES may result in physical competition with other chemokines for binding sites in the extracellular matrix. In fact, the stable binding of chemokines to the glycosaminoglycan side chain of ECM proteoglycans generates a chemotactic gradient required for the directional cell migration. Therefore, the predominance of met-RANTES distribution over the ECM would impair or limit the presence of other chemoattractants and consequently result a broader interference in chemotaxis process. However, the glycosaminoglycan-binding properties of met-RANTES remain unknown. An additional hypothesis is that the more pronounced modulation of cytokine production by the high met-RANTES doses impact as a cascade the sequential immune response, modulating differentially the local production of other chemokines that consequently impact the subsequent response. The broad and unspecific immunomodulation promoted by the high met-RANTES doses is also perceptible by the analysis of the host antimicrobial response. Indeed, our data demonstrate that MPO and IgG levels were only affected by the 5 mg dose treatment.