IL-4 Down-Regulates Anaphylatoxin Receptors in Monocytes and Dendritic Cells and Impairs Anaphylatoxin-Induced Migration In Vivo

Abstract

Anaphylatoxins mobilize leukocytes to the sites of inflammation. In the present study we investigated the impact of GM-CSF, IL-4, and IFN-γ on anaphylatoxin receptor expression in monocytes and dendritic cells (DC). IL-4 was identified as the strongest down-regulator of the receptors for C5a and C3a in monocytes and monocyte-derived DC (MoDC). To study the impact of IL-4 on anaphylatoxin-induced chemotaxis, an in vivo migration model was established. For this purpose, human monocytes and MoDC were injected i.v. into SCID mice that at the same time received anaphylatoxins into the peritoneal cavity. A peritoneal influx of human monocytes could be demonstrated by 4 h after injections of C5a and C3a. In line with receptor down-regulation, IL-4 treatment inhibited in vivo mobilization of human monocytes and MoDC in response to C5a and C3a. In addition to its effects on human cells, IL-4 reduced C5a receptors in murine bone marrow-derived DC and impaired recruitment of labeled bone marrow-derived DC in syngeneic BALB/c mice to i.p. injected C5a. Overall, these data suggest that inhibition of a rapid anaphylatoxin-induced mobilization of monocytes and DC to inflamed tissues represents an important anti-inflammatory activity of the Th2 cytokine IL-4.

β‐Defensins chemoattract macrophages and mast cells but not lymphocytes and dendritic cells: CCR6 is not involved

“…IL-4, which is commonly used for the generation of DC in vitro, was recently observed to inhibit migration of monocyte-derived macrophages and DC in response to anaphylatoxins [27]. In line with these findings, IL-4 treatment also inhibited migration of human monocytederived DC in response to b-defensins in vitro and in vivo ( Fig.…”

“…In keeping with this reasoning, IL-4, which is commonly used for the generation of human monocyte-derived DC, was identified as a suppressor of b-defensin-induced chemotaxis. This finding is reminiscent of the inhibitory effect of IL-4 on anaphylatoxin-induced DC migration as a consequence of receptor down-regulation [27].…”

“…We have recently shown that accumulation of human macrophages in the peritoneal cavity of SCID mice as a result of chemotactic cell migration was inducible by injection of anaphylatoxins and chemokines [27]. We now observed that human macrophages could be mobilized into the peritoneal cavity of SCID mice by i.p.…”

“…Recombinant (human and/or murine) CCL3, CCL19 and CCL20 were obtained from PeproTech (Cell Concepts, Umkirch, Germany). Recombinant human anaphylatoxin C5a was described elsewhere [27].…”

Vaccination and autoimmune diseases: is prevention of adverse health effects on the horizon?

“…IL4 is an anti-inflammatory cytokine involved in the cellmediated inflammatory immune response, including inhibition of monocyte and dendritic cell migration to inflamed tissue and promotion of Th2 effector pathways [148,149]. CD4+ T cell differentiation away from the Th1 pathway renders them unable to activate macrophages.…”