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

Abstract

Lactoferrin possesses a wide range of immunomodulatory activities, including promotion of the delayed type hypersensitivity response (DTH) towards BCG (Bacillus Calmette Guerin) antigens. Addition of Lactoferrin as an adjuvant to the BCG vaccine was previously demonstrated to augment protection against subsequent mycobacterial challenge, with concomitant development of a strong T cell helper type 1 (T H 1) immunity. Because generation of T H 1 immunity is in large part dependent on the balance of monocytic pro-and anti-inflammatory cytokines, the effect of Lactoferrin on leukocytes was investigated. Lactoferrin enhanced proinflammatory responses in a dose-dependant manner from splenocyte and adherent (F4/80 + ) splenocyte populations, bone marrow derived monocytes (BMM), and J774A.1 cultured cells. In all scenarios tested, Lactoferrin induced a strong increase in the ratio of IL-12:IL-10 production from LPS stimulated cells. Examination of Lactoferrin effects on BCG infected J774A.1 cells and on BMM revealed similar immunomodulatory effects, with particularly strong increase in IL-12 production. Furthermore, immunization of mice with BCG admixed with Lactoferrin led to increased generation of CD4+ cells expressing IFN-γ upon restimulation with BCG antigens. These results provide molecular evidence to support the role of Lactoferrin as an adjuvant candidate to augment development of DTH response to vaccine antigens.

Recombinant human lactoferrin expressed in glycoengineered Pichia pastoris: effect of terminal N-acetylneuraminic acid on in vitro secondary humoral immune response

“…LF could prevent MTX-induced suppression in several ways, including the induction of specific cytokines in sialoadhesin-positive splenocytes. Mediators such as IL-6 [33], IL-12 [39], and TGF-beta [7] induce anti-apoptotic responses and LF indeed increases the production of such mediators [11,19,41]. Because LF has the ability to accelerate the function of the immune system cells (reviewed in 43), it opens new perspectives for the systemic application of recombinant human LF in many immune disorders.…”

“…It is considered a first line defense protein involved in protection against microbial infections [26,31] and prevention of systemic inflammation [2,3,21]. More recently, lactoferrin has been implicated in immunoregulatory functions [19,42,44,46], as a modulator of vaccine function [18], and containing chemoprotective activity [1]. The primary structure of human LF is characterized by a single polypeptide chain containing 692 amino acids organized in two highly homologous lobes, designated the N-and C-lobe, each capable of binding one ferric ion (Fe +++ ).…”

Lactoferrin enhanced efficacy of the BCG vaccine to generate host protective responses against challenge with virulent Mycobacterium tuberculosis

“…This is known to be crucial for host protection against MTB infection [52][53][54]. Hwang, et al demonstrated in vitro that addition of lactoferrin on activated macrophages leads to increase IL-12 production while at the same time reducing IL-10 [25,33]. Together, this indicates that lactoferrin could enhance generation of mycobacterial antigen responses towards the T H 1 phenotype.…”

“…IL-12 is clearly a critical component involved in directing T H 1 development effective in promoting protective host responses during MTB infection [31,32]. More so, addition of lactoferrin to BCG infected macrophages increased the IL-12:IL-10 ratio, setting up an environment that could potentially promote BCG specific T H 1 development in vivo [25,33]. It was therefore hypothesized that lactoferrin possesses adjuvant activity that could be useful to enhance the efficacy of the BCG vaccine, leading to an increase in host protection against subsequent infection with MTB.…”

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

“…Towards its utility as an adjuvant, in vivo and in vitro studies indicate that lactoferrin can increase relative production of IL-12 while decreasing IL-10, a negative regulator of IL-12 [19,[31][32][33]. Of critical importance, bovine lactoferrin added to murine macrophages infected with BCG enhanced the production of IL-12 relative to amounts of IL-10 [34].…”