Lactoferrin down-regulates the LPS-induced cytokine production in monocytic cells via NF-κB

Håversen, Liliana; Ohlsson, Björn; Hahn-Zoric, Mirjana; Hanson, Lars Å.; Mattsby‐Baltzer, Inger

doi:10.1016/s0008-8749(03)00006-6

Cited by 310 publications

(236 citation statements)

References 52 publications

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“…22 Recently, it is reported that LPS-induced TNF-a production was suppressed by bLF through its inhibition of binding of NF-kB to the TNF-a promoter after internalization of bLF in monocytic cell. 15 It is reasonable to consider that internalized bLF may also reduce LPS-induced TNF-a and RANKL production by inhibiting the binding of NF-kB to TNF-a promoter in OBs. However, little is known about the intracellular pathways and the role of internalized bLF on OB functions, which is responsible for osteoclastogenesis.…”

Section: Discussionmentioning

confidence: 99%

“…12 bLF may also affect immunological functions by modulating the production of cytokines TNF-a, IL-1b, and IL-6, by regulating natural killer cell activity, inhibiting antibody synthesis, and maturation of T cells. [13][14][15] Although, the mechanism of bLF modulation of cytokine production is not well understood, this could be important locally at the site of inflammation, such as in the rheumatoid joint or in the periodontal tissue of the periodontitis. [16][17][18] In fact, bLF has been shown to bind 'free' iron in synovial fluid and to reduce inflammation when injected intraarticularly in mice with collagen-induced arthritis.…”

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confidence: 99%

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Inhibitory effects of orally administrated liposomal bovine lactoferrin on the LPS-induced osteoclastogenesis

Yamano

Miyauchi

Furusyo

et al. 2010

Laboratory Investigation

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Bovine lactoferrin (bLF) modulates the production of proinflammatory cytokines including tumor necrosis factor (TNF)-a, and may thus control alveolar bone destruction associated with periodontitis. In this study, the effects of bLF on mRNA expression in lipopolysaccharide (LPS)-stimulated osteoblasts (OBs) and on LPS-induced osteoclastogenesis were examined. The inhibitory effects of oral administration of liposomal-bLF (L-bLF), which improved the robustness of bLF to digestive enzymes, on alveolar bone resorption using LPS-induced periodontitis rat model are also reported. Three groups of 7-week-old male Wistar rats were treated with L-bLF (L-bLF group), bLF (bLF group), or the vehicle (control group) in drinking water (n ¼ 6 in each group). On day 7, LPS was topically applied into the gingival sulcus. Number of osteoclasts and immunoexpression of TNF-a were analyzed. The bLF inhibited the upregulation of TNF-a-mRNA-and upregulation of receptor activator of NFkB (RANKL)-mRNA expression and eliminated downregulation of osteoprotegerin (OPG)-mRNA expression in LPS-stimulated OBs and reduced LPS-induced osteoclastogenesis in co-culture with primary OBs and bone marrow cells. In the control group, the number of osteoclasts increased after LPS treatment. The number of osteoclasts that appeared along the alveolar bone margin was significantly reduced (Po0.01) in the L-bLF but not in the bLF group. Furthermore, L-bLF suppressed upregulation of TNF-a immunoexpression in periodontal tissue and TNF-a and interleukin (IL)-1b-mRNA level in gingival tissue. The results of this study indicate that oral administration of L-bLF significantly reduces alveolar bone resorption induced by LPS stimulation through inhibition of TNF-a production and modulation of RANKL/OPG balance in OBs. It is suggested that L-bLF could be a potent therapeutic and preventive agent for attenuating alveolar bone destruction in periodontitis patients.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Inhibitory effects of orally administrated liposomal bovine lactoferrin on the LPS-induced osteoclastogenesis

Yamano

Miyauchi

Furusyo

et al. 2010

Laboratory Investigation

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“…Interestingly, a small portion of the LF was found in the crude nuclear extract fraction of the cells by Western blotting. LF was reported to possess nuclear function by acting as a gene transcription factor by binding to specific DNA sequences [52] or interfering with cellular events leading to NF-κB activation or suppression [53,54]. It is not clear whether LF in the HC-11 cells entered the nucleus and suppressed proinflammatory cytokine production by interfering with NF-κB activation after LPS exposure.…”

Section: Discussionmentioning

confidence: 99%

Induction of lactoferrin gene expression by innate immune stimuli in mouse mammary epithelial HC-11 cells

Limmon

Imani

et al. 2009

Biochimie

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Lactoferrin (LF) is a multifunctional protein. While its functions and mechanism of actions are actively being investigated, the cellular signals that regulate LF expression have not been as explored. We have previously demonstrated that LF is upregulated by estrogen in reproductive system. In this study, we show that the expression of LF was stimulated by bacterial lipopolysaccharide (LPS) and double-stranded RNA (dsRNA) in normal mouse mammalian HC-11 cells. When cells were exposed to either LPS or dsRNA, the mRNA and protein of LF were increased in a dose-and time-dependent manner, yet the kinetics of LF induction by dsRNA or LPS was different. The LPS and dsRNAinduced LF was mainly released into the culture medium where it blocked TNF-α production in exposed cells. We explored the mechanisms of LF induction by LPS and dsRNA using specific inhibitors and found that the induction could be attenuated by inhibitors to PKC, NF-kB, p38 and JNK, but not by an inhibitor to PKA. Interestingly, ERK inhibitor was effective against dsRNA but not against LPS induction of LF. These data suggest that LF was induced by LPS and dsRNA through PKC, NF-kB and MAPK pathways which in turn plays an inhibitory role in the continuation of innate inflammation.

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“…[6][7][8][9] In addition to its ability to kill bacteria, lactoferrin can also neutralize endotoxin and inhibit the induction of NFkB in monocytes in response to LPS, resulting in lowered IL-6 and TNF-alpha production. [10][11][12] Lactoferrin is present in high concentrations in saliva and is thought to play a particularly important role in regulation of those bacteria present within the oral cavity. This protein regulates several bacteria that are associated with periodontal disease, including Porphyromonas gingivalis (Pg), Prevotella intermedia (Pi), Prevotella melaninogenica (Pm) and Actinobacillus actinomycetemcomitans (Aa).…”

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confidence: 99%

A nonconservative, coding single-nucleotide polymorphism in the N-terminal region of lactoferrin is associated with aggressive periodontitis in an African-American, but not a Caucasian population

et al. 2005

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Lactoferrin is an antimicrobial protein which plays an important role in regulating bacteria that are associated with aggressive periodontitis. Lactoferrin kills directly (via its strongly cationic N-terminal region) and indirectly, through sequestering the iron that bacteria require for growth. As aggressive periodontitis has a strong heritable component, we hypothesized that genetic variation within the lactoferrin gene may play a role in susceptibility to this condition. We have identified and examined a novel, functional, single-point A/G nucleotide mutation causing a threonine/alanine substitution at position 11 (T11A) of the secreted lactoferrin protein. In a pilot case-controlled study of aggressive periodontitis, analysis of 46 African-American patients and 78 controls showed that patients were twice as likely to express the G nucleotide (alanine) allele over controls (60.3 vs 30.4%; P ¼ 0.0007, odds ratio ¼ 2.564, 95% CI ¼ 1. 475-4.459). A Caucasian population of 77 patients and 131 controls showed no such association (P ¼ 0.5201, odds ratio ¼ 0.862, 95% CI ¼ 0.548-1.356). The data presented provide a new insight into the genetic susceptibility to aggressive periodontitis. Genes and Immunity (2005) Lactoferrin is an 80 kDa cationic protein with strong antibacterial and immunomodulatory functions. [1][2][3][4][5] The antibacterial properties were originally attributed solely to its ability to bind the iron necessary for bacterial growth. However, it has been established more recently that lactoferrin also binds to bacteria and kills through direct interactions governed by its strongly basic Nterminal region. [6][7][8][9] In addition to its ability to kill bacteria, lactoferrin can also neutralize endotoxin and inhibit the induction of NFkB in monocytes in response to LPS, resulting in lowered IL-6 and TNF-alpha production. [10][11][12] Lactoferrin is present in high concentrations in saliva and is thought to play a particularly important role in regulation of those bacteria present within the oral cavity. This protein regulates several bacteria that are associated with periodontal disease, including Porphyromonas gingivalis (Pg), Prevotella intermedia (Pi), Prevotella melaninogenica (Pm) and Actinobacillus actinomycetemcomitans (Aa). [13][14][15][16][17][18] Lactoferrin's effects on Aa, which is considered to have the strongest association with aggressive periodontitis, occurs through direct killing, as well as through inhibition of attachment to epithelial cells and the development of biofilms. 14,19,20 Studies examining the pattern of inheritance of aggressive periodontitis in families suggest a genetic basis for susceptibility. 18,21 The disease is particularly common within African-American populations, being up to 15 times more prevalent than in Caucasians. 21 As lactoferrin has been shown to be active against a number of pathogenic bacteria, including Aa, we hypothesized that single-nucleotide polymorphism (SNPs) within the lactoferrin gene could play a role in the genetic susceptibility that is s...

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Lactoferrin down-regulates the LPS-induced cytokine production in monocytic cells via NF-κB

Cited by 310 publications

References 52 publications

Inhibitory effects of orally administrated liposomal bovine lactoferrin on the LPS-induced osteoclastogenesis

Inhibitory effects of orally administrated liposomal bovine lactoferrin on the LPS-induced osteoclastogenesis

Induction of lactoferrin gene expression by innate immune stimuli in mouse mammary epithelial HC-11 cells

A nonconservative, coding single-nucleotide polymorphism in the N-terminal region of lactoferrin is associated with aggressive periodontitis in an African-American, but not a Caucasian population

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