Activation of macrophages by lactoferrin: secretion of TNF‐α, IL‐8 and NO

Sorimachi, Kenji; Akimoto, Kazumi; Hattori, Yoshiyuki; Ieiri, Tamio; Niwa, Akira

doi:10.1080/15216549700203841

Cited by 75 publications

(82 citation statements)

References 13 publications

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“…One main mechanism for macrophage control of intracellular BCG involves production of NO [74,75], which can be stimulated by activation with IFN-γ [76]. Also, lactoferrin alone has been shown to increase macrophage NO production [77]. However, we observed no effect of lactoferrin on intracellular proliferation of BCG.…”

Section: Discussioncontrasting

confidence: 63%

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

Hwang¹,

Kruzel

Actor³

2009

Biochimie

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The current vaccine for tuberculosis (TB), caused by Mycobacterium tuberculosis (MTB), is an attenuated strain of Mycobacterium bovis bacillus Calmette-Guerin (BCG). BCG has proven to be effective in children, however, efficacy wanes in adulthood. Lactoferrin, a natural protein with immunomodulatory properties, is a potential adjuvant candidate to enhance efficacy of BCG. These studies define bovine lactoferrin as an enhancer of the BCG vaccine, functioning in part by modulating macrophage ability to present antigen and stimulate T-cells. BCG-infected bone marrow derived macrophages (BMMs) cultured with bovine lactoferrin increased the number of MHC II + expressing cells. Addition of IFN-γ and lactoferrin to BCG-infected BMMs enhanced MHC II expressiona dna increased the ratio of CD86/CD80. Lactoferrin treated BCG-infected BMMs were able to stimulate an increase in IFN-γ production from presensitized CD3 + splenocytes. Together, these results demonstrate that bovine lactoferrin is capable of modulating BCG-infected macrophages to enhance T-cell stimulation through increased surface expression of antigen presentation and costimulatory molecules, which potentially explains the observed in vivo bovine lactoferrin enhancement of BCG vaccine efficacy to protect against virulent MTB infection.

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Section: Discussioncontrasting

confidence: 63%

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

Hwang¹,

Kruzel

Actor³

2009

Biochimie

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“…Indeed, direct stimulation of CD3+ lymphocytes by Lactoferrin does not occur (unpublished observations). Addition of Lactoferrin to naïve macrophages increased TNF-α production, a stimulatory effect that has also been reported elsewhere [42]. The effect of Lactoferrin on activated macrophages is a more complex phenomenon.…”

Section: Discussionmentioning

confidence: 61%

“…More importantly, Lactoferrin as an adjuvant is capable of enhancing the T cell mediated DTH response to a variety of antigens including Mycobacterium bovis Calmette Guerin (BCG) [27,49,50]. The primary goal of these studies was to examine, in vitro, the effect of bovine Lactoferrin on cytokine production from activated and non-activated leukocyte populations [42], with focus on defining responsive phenotypes and identifying cytokines that can drive T cell differentiation, in particular IL-12 and IL-10. The secondary goal was to establish that Lactoferrin administered with a complex vaccine antigen would result in increased production of CD4+ T helper antigen-specific responses, a subject under active investigation [18].…”

Section: Discussionmentioning

confidence: 99%

“…The goal of these studies is to examine in vitro the effect of bovine Lactoferrin on cytokine production from activated and non-activated leukocyte populations [42], with focus on adjuvant activation to elicit cytokines that can drive T cell differentiation. The effects of Lactoferrin will also be examined on BCG infected macrophages, monitoring the production of cytokine mediators that would promote the generation and stimulation of T cell immunity for use in future vaccination studies.…”

Section: Introductionmentioning

confidence: 99%

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

Hwang¹,

Wilk²,

Bangale³

et al. 2007

Med Microbiol Immunol

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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.

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“…Lactoferrin possesses a wide range of immunomodulatory activities [17][18][19] [20] [21] including promotion of the T-cell dominated DTH response towards BCG antigens [22,23], The ability of lactoferrin to enhance the generation of antigen specific DTH responses suggests that lactoferrin could promote development of specific T-cell responses against a complex antigen, such as BCG [24,25] The development of T-cell helper type 1 (T H 1) immunity is, in part, regulated by production of IL-12 [26,27]. A variety of in vivo studies have shown lactoferrin capable of increasing production of IL-12 [28][29][30].…”

Section: Introductionmentioning

confidence: 99%

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

Hwang

Wilk

Budnicka

et al. 2007

Vaccine

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Tuberculosis (TB), caused by Mycobacterium tuberculosis (MTB), is a disease with world wide consequences, affecting nearly a third of the world's population. The established vaccine for TB, an attenuated strain of Mycobacterium bovis Calmette Guerin (BCG), has existed since 1921. Lactoferrin, an iron binding protein found in mucosal secretions and granules of neutrophils was hypothesized to be an ideal adjuvant to enhance the efficacy of the BCG vaccine, specifically because of previous reports of lactoferrin enhancement of IL-12 production from macrophages infected with BCG. Different vaccination protocols were investigated for generation of host protective responses against MTB infection using lactoferrin admixed to the BCG vaccine. Resulting effects demonstrate that BCG/lactoferrin increased host protection against MTB infection by decreasing organ bacterial load and reducing lung histopathology; significant reduction in tissue CFUs and pathology were observed post challenge compared to those seen with BCG alone. Addition of lactoferrin to the vaccine led to reduced pathological damage upon subsequent infection with virulent MTB, with positive results demonstrated when admixed in oil-based vehicle (incomplete Freund's adjuvant; IFA) or when given with BCG in saline. The observed post-challenge results paralleled increasing production of IFN-γ and IL-6, but only limited changes to proinflammatory mediators TNF-α or IL-1β from BCG stimulated splenocytes. Overall, these studies indicate that lactoferrin is a useful and effective adjuvant to improve efficacy of the BCG vaccine, with potential to reduce related tissue damage and pulmonary histopathology.

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Activation of macrophages by lactoferrin: secretion of TNF‐α, IL‐8 and NO

Cited by 75 publications

References 13 publications

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

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

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

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

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