Modulation of granulocyte functions by peptide YY in the rat: age-related differences in Y receptors expression and plasma dipeptidyl peptidase 4 activity.

It has been acknowledged that aging exerts detrimental effects on cells of the innate immune system and that neuropeptides, including neuropeptide Y (NPY) and NPY-related peptides fine-tune the activity of these cells through a receptor specific mechanism. The present study investigated the age-dependent potential of peptide YY (PYY) to modulate different granulocyte functions. The PYY reduced the carrageenan-elicited granulocyte accumulation into the air-pouch of aged (24 months) rats, and markedly decreased the phagocytosis of zymosan, as well as the H(2)O(2) production, when applied in vivo (20 microg/air-pouch). The anti-inflammatory effect of PYY was less prominent in adult (8 months) and young (3 months) rats. However, the proportions of granulocytes expressing Y1, Y2 and Y5 receptor subtypes were significantly lower in both aged and young rats when compared to adult rats. Furthermore, the aging was found to be associated with the diminished dipeptidyl peptidase 4 (DP4, an enzyme converting the NPY and PYY to Y2/Y5 receptor selective agonists) activity in plasma. In conclusion, the diverse age-related anti-inflammatory effect of PYY in rats originates from different expression levels of Y1, Y2, and Y5 receptor subtypes in addition to different plasma DP4 activity.

The anti-inflammatory effect of neuropeptide Y (NPY) in rats is dependent on dipeptidyl peptidase 4 (DP4) activity and age.

Neuropeptide Y (NPY)-induced modulation of the immune and inflammatory responses is regulated by tissue-specific expression of different receptor subtypes (Y1-Y6) and the activity of the enzyme dipeptidyl peptidase 4 (DP4, CD26) which terminates the action of NPY on Y1 receptor subtype. The present study investigated the age-dependent effect of NPY on inflammatory paw edema and macrophage nitric oxide production in Dark Agouti rats exhibiting a high-plasma DP4 activity, as acknowledged earlier. The results showed that NPY suppressed paw edema in adult and aged, but not in young rats. Furthermore, plasma DP4 activity decreased, while macrophage DP4 activity, as well as macrophage CD26 expression increased with aging. The use of NPY-related peptides and Y receptor-specific antagonists revealed that anti-inflammatory effect of NPY is mediated via Y1 and Y5 receptors. NPY-induced suppression of paw edema in young rats following inhibition of DP4 additionally emphasized the role for Y1 receptor in the anti-inflammatory action of NPY. In contrast to the in vivo situation, NPY stimulated macrophage nitric oxide production in vitro only in young rats, and this effect was mediated via Y1 and Y2 receptors. It can be concluded that age-dependant modulation of inflammatory reactions by NPY is determined by plasma, but not macrophage DP4 activity at different ages.

CD45 regulates TLR-induced proinflammatory cytokine and IFN-beta secretion in dendritic cells.

CD45 is a leukocyte-specific protein tyrosine phosphatase and an important regulator of AgR signaling in lymphocytes. However, its function in other leukocytes is not well-understood. In this study, we examine the function of CD45 in dendritic cells (DCs). Analysis of DCs from CD45-positive and CD45-null mice revealed that CD45 is not required for the development of DCs but does influence DC maturation induced by TLR agonists. CD45 affected the phosphorylation state of Lyn, Hck, and Fyn in bone marrow-derived DCs and dysregulated LPS-induced Lyn activation. CD45 affected TLR4-induced proinflammatory cytokine and IFN-beta secretion and TLR4-activated CD45-null DCs had a reduced ability to activate NK and Th1 cells to produce IFN-gamma. Interestingly, the effect of CD45 on TLR-induced cytokine secretion depended on the TLR activated. Analysis of CD45-negative DCs indicated a negative effect of CD45 on TLR2 and 9, MyD88-dependent cytokine production, and a positive effect on TLR3 and 4, MyD88-independent IFN-beta secretion. This indicates a new role for CD45 in regulating TLR-induced responses in DCs and implicates CD45 in a wider regulatory role in innate and adaptive immunity.

Methionine-enkephalin modulation of hydrogen peroxide (H2O2) release by rat peritoneal macrophages involves different types of opioid receptors.

We investigated the involvement of specific types of opioid receptors in methionine-enkephalin (MET)-induced modulation of hydrogen peroxide (H2O2) release by rat macrophages primed with sub-optimal concentrations of phorbol myristate acetate (PMA). Peritoneal macrophages in vitro treated with different concentrations of MET were tested for H2O2 release in phenol red assay. In the antagonistic study macrophages were treated with MET and one opioid receptor antagonist, or combination of MET and two or three opioid receptor antagonists. MET decreased H2O2 release in eight individual macrophage samples, and increased it in 10 samples. The increase of H2O2 release induced by MET in macrophages was blocked with combination of opioid receptor antagonists specific delta1,2 and mu receptors, as well as with combination of antagonists specific for delta1,2 and kappa opioid receptors. MET-induced decrease of the H2O2 release in macrophages was prevented by opioid receptor antagonists specific for delta1,2 or mu receptors, and also with combination of two or three opioid receptor antagonists. MET-induced enhancement of H2O2 release was mediated via delta1 or delta2 opioid receptor subtypes, or by mu-kappa opioid receptor functional interactions, while MET-induced suppression involved functional interactions between delta1 and mu, delta2 and mu, or delta1 and kappa opioid receptors. It is possible that individual differences in basal or induced macrophage capacity to produce H2O2 might shape the repertoire of opioid receptors expression and in that way pre-determine the direction of MET-induced changes after the in vitro treatment.

Correlation between age-related changes in open field behavior and plaque forming cell response in DA female rats.

We investigated the relationship between immunological and behavioral changes during ageing in Dark Agouti female rats. Results showed that ageing was associated with decreased exploratory behavior and increased emotionality (open field test) and decreased pain perception (writhing assay), but not with altered depression-like behavior (forced swim test). The observed behavioral changes were paralleled with decreased innate immunity in middle-aged and old rats, as revealed by reduced peroxide production of peritoneal macrophages; and decreased specific immunity, measured by the plaque-forming cell response, in old rats in comparison with young rats. Correlation analyses between behavioral and immune parameters demonstrated a significant correlation between the lines crossed in the open field test and the plaque-forming cell response. Taken together, the demonstrated age-dependent association between exploratory behavior and specific immune response suggests a senescent decline of a common neuroimmune regulatory mechanism.