Differential effects of prophylactic, concurrent and therapeutic lactoferrin treatment on LPS-induced inflammatory responses in mice

Abstract

SUMMARYMice injected with endotoxin develop endotoxaemia and endotoxin-induced death, accompanied by the oxidative burst and overproduction of inflammatory mediators. Lactoferrin, an iron binding protein, provides a natural feedback mechanism to control the development of such metabolic imbalance and protects against deleterious effects of endotoxin. We investigated the effects of intraperitoneal administration of human lactoferrin on lipopolysaccharide (LPS)-induced release of tumour necrosis factor alpha (TNF-α ), interleukin 6 (IL-6), interleukin 10 (IL-10) and nitric oxide (NO) in vivo . Lactoferrin was administered as a prophylactic, concurrent or therapeutic event relative to endotoxic shock by intravenous injection of LPS. Inflammatory mediators were measured in serum at 2, 6 and 18 h postshock induction. Administration of lactoferrin 1 h before LPS resulted in a rather uniform inhibition of all mediators; TNF by 82%, IL-6 by 43%, IL-10 by 47% at 2 h following LPS injection,and reduction in NO (80%) at 6 h post-shock. Prophylactic administration of lactoferrin at 18 h prior to LPS injection resulted in similar decreases in TNF-α (95%) and in NO (62%), but no statistical reduction in IL-6 or IL-10. Similarly, when lactoferrin was administered as a therapeutic post-induction of endotoxic shock, significant reductions were apparent in TNF-α and NO in serum, but no significant effect was seen on IL-6 and IL-10. These results suggest that the mechanism of action for lactoferrin contains a component for differential regulation of cellular immune responses during in vivo models of sepsis.

Lactoferrin modulation of IL-12 and IL-10 response from activated murine leukocytes

“…Previous studies on LPS activated macrophages and models of sepsis also reported this inhibitory effect of Lactoferrin to moderate other proinflammatory mediators [9,37]. Certainly, the ability of Lactoferrin to inhibit LPS-induced production of TNF-α and IL-6 is present when Lactoferrin is administered prophylactically (and even therapeutically) [29], or even when given therapeutically. The anti-inflammatory effects of Lactoferrin may simply be attributed to its ability to disrupt LPS binding of CD14 [3,15].…”

Influence of bovine lactoferrin on expression of presentation molecules on BCG-infected bone marrow derived macrophages

“…There are no published reports directly examining toxicity of injected bovine lactoferrin when utilized as an adjuvant, however, high concentrations (5-10 mg/mouse) of bovine lactoferrin are often delivered in experiments examining LPS and bacterial insults in murine models of sepsis [51][52][53][54] with no overt or reported toxicity. Previous studies demonstrated that addition of lactoferrin to the BCG vaccine increased host protection against subsequent virulent MTB challenge as observed by a decrease in organ bacterial load and a reduction in pulmonary disease pathology.…”

Therapy of Experimental Pseudomonas Infections with a Nonreplicating Genetically Modified Phage

“…TNF-␣ levels peaked 1 h after LPS injection and ranged from 100 pg/ml (22) to 600 pg/ml (1) to 15,000 pg/ml (14). Reported serum IL-6 levels peaked between 2 and 4 h after LPS injection and ranged from 900 pg/ml (1) to 5,000 pg/ml (14) to 40,000 pg/ml (24). In a murine model of sepsis caused by P. aeruginosa pneumonia, serum IL-6 levels above 3,600 pg/ml were associated with 100% mortality, whereas levels below 1,200 pg/ml were associated with 100% survival (9).…”

“…Depending on the mouse strain, the source of endotoxin, and the cytokine assays used, considerable variations in the cytokine response were reported (1,14,22,24). TNF-␣ levels peaked 1 h after LPS injection and ranged from 100 pg/ml (22) to 600 pg/ml (1) to 15,000 pg/ml (14). Reported serum IL-6 levels peaked between 2 and 4 h after LPS injection and ranged from 900 pg/ml (1) to 5,000 pg/ml (14) to 40,000 pg/ml (24).…”