Lactoferrin release and interleukin-1, interleukin-6, and tumor necrosis factor production by human polymorphonuclear cells stimulated by various lipopolysaccharides: relationship to growth inhibition of Candida albicans

Abstract

Lipopolysaccharides (LPSs) from Escherichia coli, Serratia marcescens, and SabnoneUa typhimurium, at doses from 1 to 100 ng/ml, strongly enhanced growth inhibition of Candida albicans by human polymorphonuclear leukocytes (PMN) in vitro. Flow cytometry analysis demonstrated that LPS markedly augmented phagocytosis of Candida cells by increasing the number of yeasts ingested per neutrophil as well as the number of neutrophils capable of ingesting fungal cells. LPS activation caused augmented release of lactoferrin, an iron-binding protein which itself could inhibit the growth of C. albicans in vitro. Antibodies against lactoferrin effectively and specifically reduced the anti-C. albicans activity of both LPS-stimulated and unstimulated PMN.Northern (RNA blot) analysis showed enhanced production of mRNAs for interleukin-1 13, tumor necrosis factor alpha, and interleukin-6 and in neutrophils within 1 h of stimulation with LPS. The cytokines were also detected in the supernatant of the activated PMN, and their synthesis was prevented by pretreatment of LPS-stimulated PMN with protein synthesis inhibitors, such as emetine and cycloheximide. These inhibitors, however, did not block either lactoferrin release or the anti-Candida activity of LPS-stimulated PMN. These results demonstrate the ability of various bacterial LPSs to augment neutrophil function against C. albicans and suggest that the release of a candidastatic, iron-binding protein, lactoferrin, may contribute to the antifungal effect of PMN. Moreover, the ability to produce cytokines upon stimulation by ubiquitous microbial products such as the endotoxins points to an extraphagocytic, immunomodulatory role of PMN during infection.

Responsiveness of human polymorphonuclear cells (PMNL) to stimulation by a mannoprotein fraction (MP-F2) of Candida albicans; enhanced production of IL-6 and tumour necrosis factor-alpha (TNF-α) by MP-F2-stimulated PMNL from HIV-infected subjects

“…It is of interest that mannoprotein, LPS, and various other immunomodulatory molecules of microbial source are generated by common, abundant intestinal microorganisms which may increase their burden and cause a number of opportunistic infections in AIDS patients. In particular, MP-F2-like molecules may circulate to a substantial level in certain AIDS patients [30], and the C. albicans cells themselves have been reported to stimulate cytokine production by PMNL and monocyte-macrophage cells in vitro [8][9][10]31].…”

“…Some of the PMNL-produced cytokines, e.g. TNF-a, are, in turn, strong activators of the antimicrobial activity of PMNL, thus initiating what appears to be a virtuous antimicrobial circle of autocrine-paracrine PMNL activity [6][7][8].…”

“…One of the most effective PMNL activators is a mannoprotein fraction of Candida albicans, designated MP-F2 [9][10][11], which induces lactoferrin secretion and causes growth inhibition of lactoferrin-sensitive microorganisms [8,12]. Candida albicans itself is a human commensal and opportunistic pathogen which causes very frequent, extensive infections of the mucosa (oropharingeal, oesophageal, vaginal) in subjects infected by HIV [13,15].…”

“…Probably through the mediation of MP-F2, the whole fungal cell is a strong PMNL activator [8,12]. Despite the increased awareness of the continuous exposure of the HIV + subject to colonization and infection by C. albicans, and the well known immunomodulatory effects of fungal components, the cytokine response by PMNL of HIV + subjects to the fungal cell and its immunomodulatory products has been very little explored.…”

Anti‐Candida Activity of Cal protect in in Combination with Neutrophils or Lactoferrin

“…The anti-Candida activity of neutrophils can be regulated by various immunomodulators: bacterial lipopolysaccharide (LPS) and cytokines such as TNF and IL-8 augment the anti-Candida activity of neutrophils, while glucocorticoids and progesterone diminish it (9,10,18). Furthermore, several endogenous molecules, such as reactive oxygens, nitric oxide, lactoferrin and calprotectin, were suggested to have roles in the anti-Candida activity of neutrophils (4,6,12,14,16). The cooperative activity of neutrophils and related molecules should be studied to elucidate the host defense against Candida infection.…”