Bovine Lactoferrin Free of Lipopolysaccharide Can Induce a Proinflammatory Response of Macrophages

Overview

Journal BMC Vet Res

Publisher Biomed Central

Specialty Veterinary Medicine

Date 2016 Nov 11

PMID 27829421

Citations 16

Authors

Nada Zemankova

Katarina Chlebova

Jan Matiasovic

Jana Prodelalova

Jan Gebauer

Martin Faldyna

Affiliations

Soon will be listed here.

Abstract

Background: Lactoferrin (LF) is an 80 kDa glycoprotein which is known for its effects against bacteria, viruses and other pathogens. It also has a high potential in nutrition therapy and welfare of people and a variety of animals, including piglets. The ability to bind lipopolysaccharide (LPS) is one of the described anti-inflammatory mechanisms of LF. Previous studies suggested that cells can be stimulated even by LPS-free LF. Therefore, the aim of our study was to bring additional information about this possibility. Porcine monocyte derived macrophages (MDMF) and human embryonic kidney (HEK) cells were stimulated with unpurified LF in complex with LPS and with purified LF without bound LPS.

Results: Both cell types were stimulated with unpurified as well as purified LF. On the other hand, neither HEK0 cells not expressing any TLR nor HEK4a cells transfected with TLR4 produced any pro-inflammatory cytokine transcripts after stimulation with purified LF. This suggests that purified LF without LPS stimulates cells via another receptor than TLR4. An alternative, TLR4-independent, pathway was further confirmed by analyses of the NF-kappa-B-inducing kinase (NIK) activation. Western blot analyses showed NIK which activates different NFκB subunits compared to LF-LPS signaling via TLR4. Though, this confirmed an alternative pathway which is used by the purified LF free of LPS. This stimulation of MDMF led to low, but significant amounts of pro-inflammatory cytokines, which can be considered as a positive stimulation of the immune system.

Conclusion: Our results suggest that LF's ability is not only to bind LPS, but LF itself may be a stimulant of pro-inflammatory pathways.

Citing Articles

Immunologic Effects of a Novel Bovine Lactoferrin-Derived Peptide on the Gut and Clinical Perspectives.

Cui H, Yang H, Qi X, Zhao Y, Huang T, Miao L Vet Sci. 2024; 11(11).

PMID: 39591319 PMC: 11599047. DOI: 10.3390/vetsci11110545.

Looking Inside of the Intestinal Permeability Regulation by Protein-Derivatives from Bovine Milk.

Guzman-Mejia F, Molotla-Torres D, Godinez-Victoria M, Valdes-Hilarios X, Sanchez-Miranda E, Oros-Pantoja R Mol Nutr Food Res. 2024; 68(22):e2400384.

PMID: 39530631 PMC: 11605791. DOI: 10.1002/mnfr.202400384.

Immunomodulatory effect of bovine lactoferrin during SARS-CoV-2 infection.

da Silva A, Machado T, Nascimento R, Rodrigues M, Coelho F, Tubarao L Front Immunol. 2024; 15:1456634.

PMID: 39483459 PMC: 11524939. DOI: 10.3389/fimmu.2024.1456634.

The immunomodulatory effects of lactoferrin and its derived peptides on NF-κB signaling pathway: A systematic review and meta-analysis.

Yami H, Tahmoorespur M, Javadmanesh A, Tazarghi A, Sekhavati M Immun Inflamm Dis. 2023; 11(8):e972.

PMID: 37647433 PMC: 10413819. DOI: 10.1002/iid3.972.

Characterization of Porcine Monocyte-Derived Macrophages Cultured in Serum-Reduced Medium.

Stepanova H, Kavanova L, Leva L, Vicenova M, Stastny K, Faldyna M Biology (Basel). 2022; 11(10).

PMID: 36290361 PMC: 9598231. DOI: 10.3390/biology11101457.

References

Zarnegar B, Yamazaki S, He J, Cheng G . Control of canonical NF-kappaB activation through the NIK-IKK complex pathway. Proc Natl Acad Sci U S A. 2008; 105(9):3503-8. PMC: 2265190. DOI: 10.1073/pnas.0707959105. View

Zhou Y, Zeng Z, Zhang W, Xiong W, Wu M, Tan Y . Lactotransferrin: a candidate tumor suppressor-Deficient expression in human nasopharyngeal carcinoma and inhibition of NPC cell proliferation by modulating the mitogen-activated protein kinase pathway. Int J Cancer. 2008; 123(9):2065-72. DOI: 10.1002/ijc.23727. View

Hosoda H, Tamura H, Kida S, Nagaoka I . Transcriptional regulation of mouse TREM-1 gene in RAW264.7 macrophage-like cells. Life Sci. 2011; 89(3-4):115-22. DOI: 10.1016/j.lfs.2011.05.007. View

Stepanova H, Pavlova B, Stromerova N, Ondrackova P, Stejskal K, Slana I . Different immune response of pigs to Mycobacterium avium subsp. avium and Mycobacterium avium subsp. hominissuis infection. Vet Microbiol. 2012; 159(3-4):343-50. DOI: 10.1016/j.vetmic.2012.04.002. View

Nguyen D, Jiang P, Stensballe A, Bendixen E, Sangild P, Chatterton D . Bovine lactoferrin regulates cell survival, apoptosis and inflammation in intestinal epithelial cells and preterm pig intestine. J Proteomics. 2016; 139:95-102. DOI: 10.1016/j.jprot.2016.03.020. View

Hetherington S, Spitznagel J, Quie P . An enzyme-linked immunoassay (ELISA) for measurement of lactoferrin. J Immunol Methods. 1983; 65(1-2):183-90. DOI: 10.1016/0022-1759(83)90314-9. View

Xiao G, Harhaj E, Sun S . NF-kappaB-inducing kinase regulates the processing of NF-kappaB2 p100. Mol Cell. 2001; 7(2):401-9. DOI: 10.1016/s1097-2765(01)00187-3. View

Malinin N, Boldin M, Kovalenko A, Wallach D . MAP3K-related kinase involved in NF-kappaB induction by TNF, CD95 and IL-1. Nature. 1997; 385(6616):540-4. DOI: 10.1038/385540a0. View

Zemann N, Klein P, Wetzel E, Huettinger F, Huettinger M . Lactoferrin induces growth arrest and nuclear accumulation of Smad-2 in HeLa cells. Biochimie. 2010; 92(7):880-4. DOI: 10.1016/j.biochi.2010.03.013. View

10.

Oeckinghaus A, Hayden M, Ghosh S . Crosstalk in NF-κB signaling pathways. Nat Immunol. 2011; 12(8):695-708. DOI: 10.1038/ni.2065. View

11.

Choi B, Actor J, Rios S, dAnjou M, Stadheim T, Warburton S . Recombinant human lactoferrin expressed in glycoengineered Pichia pastoris: effect of terminal N-acetylneuraminic acid on in vitro secondary humoral immune response. Glycoconj J. 2008; 25(6):581-93. PMC: 2551750. DOI: 10.1007/s10719-008-9123-y. View

12.

Pammi M, Abrams S . Oral lactoferrin for the prevention of sepsis and necrotizing enterocolitis in preterm infants. Cochrane Database Syst Rev. 2015; (2):CD007137. DOI: 10.1002/14651858.CD007137.pub4. View

13.

Puddu P, Carollo M, Belardelli F, Valenti P, Gessani S . Role of endogenous interferon and LPS in the immunomodulatory effects of bovine lactoferrin in murine peritoneal macrophages. J Leukoc Biol. 2007; 82(2):347-53. DOI: 10.1189/jlb.1106688. View

14.

Hwang S, Kruzel M, Actor J . Immunomodulatory effects of recombinant lactoferrin during MRSA infection. Int Immunopharmacol. 2014; 20(1):157-63. PMC: 4017373. DOI: 10.1016/j.intimp.2014.02.029. View

15.

Manzoni P, De Luca D, Stronati M, Jacqz-Aigrain E, Ruffinazzi G, Luparia M . Prevention of nosocomial infections in neonatal intensive care units. Am J Perinatol. 2013; 30(2):81-8. DOI: 10.1055/s-0032-1333131. View

16.

Bagwe S, Tharappel L, Kaur G, Buttar H . Bovine colostrum: an emerging nutraceutical. J Complement Integr Med. 2015; 12(3):175-85. DOI: 10.1515/jcim-2014-0039. View

17.

Hung Y, Yang Y, Wang H, Liao J, Hsu W, Chang C . Bovine lactoferrin and piroxicam as an adjunct treatment for lymphocytic-plasmacytic gingivitis stomatitis in cats. Vet J. 2014; 202(1):76-82. DOI: 10.1016/j.tvjl.2014.06.006. View

18.

Hayakawa T, Harada H, Noda A, Kondo T . Lactoferrin in pure pancreatic juice in chronic pancreatitis. Am J Gastroenterol. 1983; 78(4):222-4. View

19.

Fullard R, Snyder C . Protein levels in nonstimulated and stimulated tears of normal human subjects. Invest Ophthalmol Vis Sci. 1990; 31(6):1119-26. View

20.

Hwang S, Kruzel M, Actor J . Influence of bovine lactoferrin on expression of presentation molecules on BCG-infected bone marrow derived macrophages. Biochimie. 2008; 91(1):76-85. PMC: 2626195. DOI: 10.1016/j.biochi.2008.04.008. View