Assignment

Assignment

Introduction

IL-6 is a pleiotropic cytokine implicated in the pathogenesis of disorders such as sepsis and cancer. We noted that human monocytes are excellent producers of IL-6 as compared with monocyte-derived macrophages. Because macrophages from molecule containing ankyrin repeats induced by LPS (MAIL) knockout animals have suppressed IL-6 production, we hypothesized that regulation of MAIL is key to IL-6 production in humans and may explain the differences between human monocytes and macrophages. To test this hypothesis fresh human monocytes and monocyte-derived macrophages were compared for MAIL expression in response to LPS. LPS-induced monocyte MAIL expression was highly inducible and transient. Importantly for our hypothesis MAIL protein expression was suppressed during differentiation of monocytes to macrophages. Of note, the human MAIL protein detected was the 80 kDa MAIL-L forms and human MAIL showed nuclear localization.

MAIL regulates human monocyte IL-6 production

Innate immunity involving mainly monocytes and macrophages is considered an important defense mechanism against pathogenic fungi involved in systemic mycoses. These phagocytes play a key role in host defense by ingestion and inactivation of invading organisms, cytokine production, and interactions with other cells participating in adaptive immunity such as T and B lymphocytes 1 2.

Macrophage activation is one of the first events in innate resistance to intracellular infection. These cells can be classically activated by prototypical stimuli as IFN-gamma and LPS, and alternatively activated after exposure to IL-4 or IL-13, IL-10, TGF-beta or glucocorticoids, and immune complexes in combination with IL-1 beta or LPS 3. Interaction of macrophages with intracellular pathogens that express one or more PAMPs (pathogen-associated molecular patterns), provides a signal which stimulates macrophage activation through toll-like receptors (TLRs) 4. These stimuli generally induce the activation and secretion of inflammatory cytokines 4 5. Thus, monocytes play a pivotal role in immune regulation by production of tumor necrosis factor (TNF-agr), interleukin (IL)-1, IL-6, IL-8, IL-10, IL-12 and transforming growth factor beta (TGF-ß) 6-8. These cytokines may modulate monocyte and macrophage functions by stimulating or inhibiting the oxidative and non-oxidative microbicidal activities of these cells in an autocrine and paracrine fashion 4 9-11. The imbalance in pro- and anti-inflammatory cytokine production by these cells during infection with pathogenic fungi may determine the disease progression or microorganism death.

In vitro studies on human monocyte/macrophage-fungal interactions, such as those involving Coccidioides immitis 12, Cryptococcus neoformans 13, Candida albicans 14, Malassezia spp. 15 16, and Paracoccidioides brasiliensis 17 have shown the production of several inflammatory and deactivating cytokines after fungus stimulation confirming these phagocytes as an important cytokine source during fungal interactions.

Cell wall or capsule components of pathogenic fungi such as C. neoformans have been studied and related to cytokine production, and host immune response modulation. The stimulation of monocytes with glucuronoxylomannan, galactoxylomannan and mannoprotein, some capsule constituents of the fungus, led to TNF-agr, IL-6, and IL-10 synthesis by these cells 18-21.

Interleukin-6 production has been reported in fungal infections by C. albicans 22, C. immitis 23 and P. brasiliensis 24 25. In human disseminated candidiasis, high levels of IL-6 have been associated with disease severity and related ...