Interleukin (IL)-13 is a newly described cytokine expressed by activated lymphocytes. We examined the effects of the murine recombinant cytokine on the phenotype and activation status of elicited peritoneal macrophages (M phi), concentrating on activities which are known to be modulated by interferon-gamma and IL-4. IL-13 markedly suppressed nitric oxide release and to a lesser extent secretion of the pro-inflammatory cytokine tumor necrosis factor-alpha. However, antimicrobial capacity was not completely jeopardized as the respiratory burst was unaffected, and indeed the enhanced expression of M phi mannose receptor and major histocompatibility class II, and regulation of sialoadhesin, the M phi sialic acid-specific receptor involved in hemopoietic and lymphoid interactions, suggest that these cells are not simply deactivated, but primed for an active role in immune and inflammatory responses. These activities closely mimic those of IL-4, but mediation of the effects by IL-4 was discounted by the use of a neutralizing monoclonal antibody. Thus, IL-13, like IL-4, is a cytokine which has complex effects on M phi behavior, inducing activities characteristic of both activation and deactivation.
SummaryRegulation of macrophage scavenger receptor (MSR) activity may be an important determinant of the extent of atherogenesis. The effect of macrophage-colony-stimulating factor (M-CSF) on this pathway was studied using a recently developed monoclonal antibody to murine MSR. M-CSF markedly and selectively increased MSR synthesis in murine macrophages: posttranslationally, the receptor appeared more stable and shifted to a predominantly surface distribution. Functionally, M-CSF enhanced modified lipoprotein uptake and increased divalent cationindependent adhesion in vitro. These results suggest a plausible mechanism whereby M-CSF production in the atheromatous plaque microenvironment could promote the recruitment and retention of mononuclear phagocytes and subsequent foam cell formation.M acrophages (MO) serve as the principal inflammatory . cell in the atheromatous plaque microenvironment. The macrophage scavenger receptor (MSR) mediates modified lipoprotein-cholesterol uptake and subsequent cholesteryl ester accumulation and foam cell formation (1) and the regulation of MSR expression and activity therefore represents an important determinant of the extent of atherogenesis.M-CSF treatment in patients with hematological disease coincides with significant reductions in serum cholesterol levels. As M-CSF enhances acetyhted low-density lipoprotein (AcLDL) uptake and degradation in human monocyte-derived MO (2), the MSR pathway has been nonspecifically implicated in this observed reduction in serum cholesterol. Scavenger receptor activity is however also expressed by endothdiai, Kupffer, and liver parenchymal cells (3, 4) as well as by phorbol esterinduced fibroblasts and smooth muscle cells (5). Molecules other than the macrophage-specific MSR may mediate these properties. Furthermore, other MO receptors such as the thrombospondin receptor (CD36) and the IgG Fc receptor (Fc'/RII-B2; CD32) are capable of mediating uptake of oxidized lipoprotein (6, 7). Characterization of MSR regulation and expression has been hampered by the lack of specific reagents.Both human and rabbit atherosclerotic lesions contain M-CSF mRNA and immunoreactive M-CSF (8, 9). Vascular endothelial cells and smooth muscle cells produce M-CSF in response to a range of stimuli, including modified LDL (10). In addition, a novel function for the MSR as an adhesion receptor was recently described (11); this stemmed from Portions of this work were submitted in abstract form to the January 1994
RT-PCR was used to examine the expression of IFN-gamma, IL-2, IL-4, IL-5, IL-6 and IL-10 mRNAs by single murine CD4+ T cells activated either in a strongly type 1-polarized mixed lymphocyte reaction (MLR) or in the type 2-polarized response to immunization with keyhole limpet hemocyanin (KLH) in alum. The frequencies of expression of each cytokine differed markedly between the two responses, consistent with their polarization at the population level. However, most cells expressed only none to three of the six cytokines assayed, few displayed the canonical type 1 profile and none in either response expressed a full type 2 or type 0 profile. A significant fraction of cells co-expressed IFN-gamma with IL-4 and/or other type 2 cytokines at frequencies that suggested that most of these genes were independently regulated. Collectively, these single-cell expression patterns indicate that polarization at the population level can mask substantial intercellular heterogeneity, and show directly that multiple type 1 and 2 cytokines can be expressed simultaneously in an individual T cell.
SummaryThe mechanisms by which cellular immunity maintains the asymptomatic state after human immunodeficiency virus type 1 (HIV-1) infection are poorly understood. CD4 + T lymphocytes play a complex role in regulating anti-HIV effector pathways, including activation of macrophages, which are themselves implicated in clinical latency and pathogenesis of symptomatic acquired immune deficiency syndrome. We have found that a newly identified T helper type 2 lymphokine, interleukin 13 (IL-13), inhibits HIV-I~^ and B~-L replication in primary tissue culture-derived macrophages but not in peripheral blood lymphocytes. Viral production in cells was measured by viral protein (p24) and reverse transcriptase levels, while entry was assessed by proviral DNA analysis at timed intervals after infection. Inhibition by IL-13 was dose and time dependent and not mediated through altered viral entry, reverse transcription, or viral release. IL-13 is therefore a candidate cytokine for the suppression of HIV infection within monocytes and macrophages in vivo.
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