Differential Regulation of CXCR4 and CCR5 Expression by Interleukin (IL)-4 and IL-13 Is Associated with Inhibition of Chemotaxis and Human Immunodeficiency Virus (HIV) Type 1 Replication But Not HIV Entry into Human Monocytes

Abstract

Chemokine receptors CXCR4 and CCR5 play a key role in Human Immunodeficiency Virus (HIV) entry into CD4+ monocytic cells. Alteration in the expression levels of these receptors by immunoregulatory cytokines may influence viral entry and hence susceptibility to HIV infection, viral tropism, and disease progression. Helper T cell type 2 (Th2) cytokines interleukin (IL)-4 and IL-13, which share a subunit of their receptor components and exhibit similar biological effects, have been shown to play a key role in HIV infection and disease progression. In this study, we investigated the effects of IL-4 and IL-13 on the expression of CXCR4 and CCR5, and the biological implications of alteration of CXCR4 and CCR5 regulation on monocytic cells with respect to their migration in response to chemokines, HIV entry, and its replication. The results suggest that both IL-4 and IL-13 inhibited the expression of CXCR4, in contrast to CCR5, which was inhibited by IL-13 alone. The downregulation of CXCR4 and CCR5 was correspondingly associated with the inhibition of their respective ligand-induced chemotaxis. Although IL-13 inhibited the expression of both CXCR4 and CCR5, this downregulation of chemokine receptor expression was not sufficient to prevent virus entry. Furthermore, both IL-4 and IL-13 inhibited viral replication in monocytic cells, suggesting that inhibition of chemokine receptor expression per se by these cytokines may not be sufficient to prevent virus entry, and indicating these cytokines may be inhibiting viral replication by targeting pathways subsequent to virus entry.

Different proliferative and survival capacity of CLL-cells in a newly established in vitro model for pseudofollicles

“…31 A similar CXCR4 down-regulating effect of IL-4 was recently shown on human monocytes. 32 Lower CXCR4 expression was identified on lymph node-infiltrating CLL-cells compared with peripheral blood CLL-cells, 33 which may reflect an in vivo IL-4 effect besides the CXCL12-induced receptor endocytosis. 34 Bone marrow stromal cells express IL-4R 35 and on IL-4 stimulation they up-regulate VCAM1, 36 therefore IL-4 may also exert an indirect effect on CLL-cells through BMSCs.…”

“…One group of non-proliferating cases (NP/1) with unmutated IgV H (Pat 16, 19, 21, 31) and/or peripheral blood lymphocytosis above 5 Â 10 4 /ml (Pat 13, 27) also showed higher survival rates in medium (similar to the proliferating cases) than cells from indolent cases (NP/2) with mutated IgV H and lower lymphocyte counts (Pat 12,14,15,18,22,30,32) (Figures 5b-d). Interestingly, CLL-cells from indolent cases benefited more from BMSCs than proliferating cases, although this difference was not statistically significant (Figure 5b).…”

Antimicrobial implications of vitamin D

“…Promoting a predominantly Th2 response will induce release of cytokines (such as IL-13) known to downregulate CCR5 expression. 68 Vitamin D also regulates production of RANTES, 3 a natural ligand of CCR5 whose binding helps block viral entry. Highly active antiretroviral therapy may be linked to significant changes in vitamin D status.…”

Characterization of the Early Steps of Infection of Primary Blood Monocytes by Human Immunodeficiency Virus Type 1

“…Monocytes express both CD4 receptor and CCR5 and CXCR4 coreceptors (9,10,14,20,21,29,39,40), and poor infection of monocytes is also observed with viral particles pseudotyped with pantropic envelopes, such as the vesicular stomatitis virus G protein (VSVg) (37,43). The identity of this block remains, however, controversial.…”