Sandra Gessani

IFN-γ Expression in Macrophages and Its Possible Biological Significance

Abstract IFN- γ is a pleiotropic cytokine endowed with potent immunomodulatory effects whose expression was long considered to be restricted to T and NK cells. Only recently, it became evident that IFN- γ production can also occur in other cell types, including monocyte\macrophages. However, the biological relevance of macrophage IFN- γ is still unclear. The purpose of this article is to provide an overview of the collected evidence demonstrating IFN- γ expression in macrophages and to discuss the possible biological significance of this cytokine production in the early phase of host response to infectious agents.

Human Immunodeficiency Virus Type 1 gp120 Induces Abnormal Maturation and Functional Alterations of Dendritic Cells: a Novel Mechanism for AIDS Pathogenesis

ABSTRACT Dendritic cells (DCs) play a crucial role in bridging innate and acquired immune responses to pathogens. In human immunodeficiency virus type 1 (HIV-1) infection, immature DCs (iDCs) are also main targets for HIV-1 at the mucosal level. In this study, we evaluated the effects of HIV-1-DC interactions on the maturation and functional activity of these cells. Exposure of human monocyte-derived iDCs to either aldrithiol-2-inactivated HIV-1 or gp120 led to an upmodulation of activation markers indicative of functional maturation. Despite their phenotype, these cells retained antigen uptake capacity and showed an impaired ability to secrete cytokines or chemokines and to induce T-cell proliferation. Although gp120 did not interfere with DC differentiation, the capacity of these cells to produce interleukin-12 (IL-12) upon maturation was markedly reduced. Likewise, iDCs stimulated by classical maturation factors in the presence of gp120 lacked allostimulatory capacity and did not produce IL-12, in spite of their phenotype typical of activated DCs. Exogenous addition of IL-12 restores the allostimulatory capacity of gp120-exposed DCs. The finding that gp120 induces abnormal maturation of DCs linked to profound suppression of their activities unravels a novel mechanism by which HIV can lead to immune dysfunction in AIDS patients.

Antiviral Activity of Lactoferrin

In 1976, Matthews et al.19 reported the antiviral activity of milk proteins, underlining their possible clinical importance. Only recently, this effect has been ascribed mainly to lactoferrin (Lf). Lf was initially shown to exert a protective influence in mice infected with Friend leukemia virus15. Subsequently, a potent antiviral activity has been attributed to Lf, both in vitro towards cytomegalovirus (HCMV)9,7, herpes simplex virus (HSV)17, human immunodeficiency virus (HIV)7,29 and in vivo towards HSV-16 and HCMV25. Our groups provided evidence on the antiviral activity of Lf towards HSV-218, rotavirus28, and HIV22 infections (Table 1).

Dual Role of the HIV-1 Vpr Protein in the Modulation of the Apoptotic Response of T Cells

We investigated the effect of vpr, physiologically expressed during the course of an acute HIV-1 infection, on the response of infected cells to apoptotic stimuli as well as on the HIV-induced apoptosis. At 48 h after infection, Jurkat cells exhibited a lower susceptibility to undergo apoptosis with respect to uninfected cells. This effect was not observed following infection with either a vpr-mutated virus or a wild-type strain in the presence of antisense oligodeoxynucleotides targeted at vpr mRNA. Single-cell analysis, aimed at simultaneously identifying apoptotic and infected cells, revealed that resistance to apoptosis correlated with productive infection. Notably, vpr-dependent protection from induced apoptosis was also observed in HIV-1-infected PBMC. In contrast, at later stages of infection, a marked increase in the number of cells spontaneously undergoing apoptosis was detected in infected cultures. This virus-induced apoptosis involved vpr expression and predominantly occurred in productively infected cells. These results indicate that HIV-1 vpr can exert opposite roles in the regulation of apoptosis, which may depend on the level of its intracellular expression at different stages of HIV-1 infection. The dual function of vpr represents a novel mechanism in the complex strategy evolved by HIV to influence the turnover of T lymphocytes leading to either viral persistence or virus release and spreading.

IFN‐α and IL‐18 exert opposite regulatory effects on the IL‐12 receptor expression and IL‐12‐induced IFN‐γ production in mouse macrophages: novel pathways in the regulation of the inflammatory response of macrophages

We characterized the IL‐12 response of mouse macrophages in terms of modulation of IFN‐γ production by cytokines (IFN‐α and IL‐18) and regulation of IL‐12 receptor expression. β1 and β2 IL‐12R chain mRNA expression increased with time in culture in the absence of exogenous stimulation, with concomitant acquisition of responsiveness to IL‐12 for IFN‐γ production. Expression of the IL‐12R β1 chain mRNA was increased further following IL‐12 treatment as a consequence of IFN‐γ expression. IL‐12 response was regulated differentially by IFN‐α and IL‐18. Neutralization of endogenous type I IFN increased IFN‐γ secretion, whereas exogenous IFN‐α reduced it. In contrast, IL‐18 enhanced IFN‐γ mRNA accumulation and IFN‐γ secretion in IL‐12‐stimulated, but not ‐untreated, cultures. The opposite effects exerted by IFN‐α and IL‐18 mirror their mutual capacity of regulating—in a negative or positive manner, respectively—the expression of the IL‐12R β1 chain. We suggest that differential regulation of IL‐12 response by IFN‐α and IL‐18 can represent previously unrecognized regulatory mechanisms for maintaining suitable levels of differentiation/activation in macrophages.

LF immunomodulatory strategies: mastering bacterial endotoxin.

Lactoferrin (LF), an iron-binding glycoprotein expressed in most biological fluids, represents a major component of mammalian innate immune system. The multiple activities of LF rely not only on its capacity to bind iron but also to interact with molecular and cellular components of both the host and pathogens. LF can bind and sequester lipopolysaccharide thus preventing proinflammatory pathway activation, sepsis, and tissue damage. However, the interplay between LF and lipopolysaccharide is complex and may lead to different outcomes including both the suppression of inflammatory response and immune activation. Understanding the molecular basis and the functional consequences of this complex interaction is critically relevant in the development of LF-based therapeutic interventions in humans.

Reciprocal Interactions between Lactoferrin and Bacterial Endotoxins and Their Role in the Regulation of the Immune Response

Lactoferrin (Lf), an iron-binding glycoprotein expressed in most biological fluids, represents a major component of the mammalian innate immune system. Lf’s multiple activities rely not only on its capacity to bind iron, but also to interact with molecular and cellular components of both host and pathogens. Lf can bind and sequester lipopolysaccharide (LPS), thus preventing pro-inflammatory pathway activation, sepsis and tissue damage. However, Lf-bound LPS may retain the capacity to induce cell activation via Toll-like receptor 4-dependent and -independent mechanisms. This review discusses the complex interplay between Lf and LPS and its relevance in the regulation of the immune response.

Type I Interferons as Regulators of Human Antigen Presenting Cell Functions

Type I interferons (IFNs) are pleiotropic cytokines, initially described for their antiviral activity. These cytokines exhibit a long record of clinical use in patients with some types of cancer, viral infections and chronic inflammatory diseases. It is now well established that IFN action mostly relies on their ability to modulate host innate and adaptive immune responses. Work in recent years has begun to elucidate the mechanisms by which type I IFNs modify the immune response, and this is now recognized to be due to effects on multiple cell types, including monocytes, dendritic cells (DCs), NK cells, T and B lymphocytes. An ensemble of results from both animal models and in vitro studies emphasized the key role of type I IFNs in the development and function of DCs, suggesting the existence of a natural alliance between these cytokines and DCs in linking innate to adaptive immunity. The identification of IFN signatures in DCs and their dysregulation under pathological conditions will therefore be pivotal to decipher the complexity of this DC-IFN interaction and to better exploit the therapeutic potential of these cells.

Gender-related differences in lifestyle may affect health status

Consistent epidemiological and clinical evidence strongly indicates that chronic non-communicable diseases are largely associated with four lifestyle risk factors: inadequate diet, physical inactivity, tobacco use, and excessive alcohol use. Notably, obesity, a worldwide-growing pathological condition determined by the combination between inadequate diet and insufficient physical activity, is now considered a main risk factor for most chronic diseases. Dietary habits and physical activity are strongly influenced by gender attitudes and behaviors that promote different patterns of healthy or unhealthy lifestyles among women and men. Furthermore, different roles and unequal relations between genders strongly interact with differences in social and economic aspects as well as cultural and societal environment. Because of the complex network of factors involved in determining the risk for chronic diseases, it has been promoting a systemic approach that, by integrating sex and gender analysis, explores how sex-specific biological factors and gender-related social factors can interact to influence the health status.

Linking estrogen receptor β expression with inflammatory bowel disease activity.

Crohn disease (CD) and ulcerative colitis (UC) are chronic forms of inflammatory bowel disease (IBD) whose pathogenesis is only poorly understood. Estrogens have a complex role in inflammation and growing evidence suggests that these hormones may impact IBD pathogenesis. Here, we demonstrated a significant reduction (p < 0.05) of estrogen receptor (ER)β expression in peripheral blood T lymphocytes from CD/UC patients with active disease (n = 27) as compared to those in remission (n = 21) and healthy controls (n = 29). Accordingly, in a subgroup of CD/UC patients undergoing to anti-TNF-α therapy and responsive to treatment, ERβ expression was higher (p < 0.01) than that observed in not responsive patients and comparable to that of control subjects. Notably, ERβ expression was markedly decreased in colonic mucosa of CD/UC patients with active disease, reflecting the alterations observed in peripheral blood T cells. ERβ expression inversely correlated with interleukin (IL)-6 serum levels and exogenous exposure of both T lymphocytes and intestinal epithelial cells to this cytokine resulted in ERβ downregulation. These results demonstrate that the ER profile is altered in active IBD patients at both mucosal and systemic levels, at least in part due to IL-6 dysregulation, and highlight the potential exploitation of T cell-associated ERβ as a biomarker of endoscopic disease activity.