Top

BMC Oral Health

Published in:

Open Access 01-12-2021 | Research

RNAseq of TGF-β receptor type I kinase-dependent genes in oral fibroblast exposed to milk

Authors: Layla Panahipour, Dariush Mehdipour Moghaddam, Jila Nasirzade, Zahra Kargarpour, Reinhard Gruber

Published in: BMC Oral Health | Issue 1/2021

Abstract

Background

Milk is a rich source of natural growth factors that may support oral tissue homeostasis and wound healing. We had shown earlier that blocking TGF-β receptor type I kinase with the inhibitor SB431542 abolished the expression of IL11 and other genes in human gingival fibroblasts exposed to the aqueous fraction of milk. Our aim was to identify the entire signature of TGF-β receptor type I kinase-dependent genes regulated by the aqueous fraction of human milk.

Result

RNAseq revealed 99 genes being strongly regulated by milk requiring activation of the SB431542-dependent TGF-β receptor type I kinase. Among the SB431542-dependent genes is IL11 but also cadherins, claudins, collagens, potassium channels, keratins, solute carrier family proteins, transcription factors, transmembrane proteins, tumor necrosis factor ligand superfamily members, and tetraspanin family members. When focusing on our candidate gene, we could identify D609 to suppress IL11 expression, independent of phospholipase C, sphinosine-1 phosphate synthesis, and Smad-3 phosphorylation and its nuclear translocation. In contrast, genistein and blocking phosphoinositide 3-kinases by wortmannin and LY294002 increased the milk-induced IL11 expression in gingival fibroblasts.

Conclusion

Taken together, our data revealed TGF-β receptor type I kinase signaling to cause major changes of the genetic signature of gingival fibroblasts exposed to aqueous fraction of human milk.

Available only for authorised users

Goldman AS. Evolution of immune functions of the mammary gland and protection of the infant. Breastfeed Med. 2012;7(3):132–42.PubMedCrossRef

Panahipour L, Kochergina E, Kreissl A, Haiden N, Gruber R. Milk modulates macrophage polarization in vitro. Cytokine: X. 2018;1(2):100009.

Panahipour L, Nasserzare S, Amer Z, Brucke F, Stahli A, Kreissl A, Haiden N, Gruber R. The anti-inflammatory effect of milk and dairy products on periodontal cells: an in vitro approach. Clin Oral Investig. 2019;23(4):1959–66.PubMedCrossRef

Gila-Diaz A, Arribas SM, Algara A, Martin-Cabrejas MA, Lopez de Pablo AL, Saenz de Pipaon M, Ramiro-Cortijo D. A review of bioactive factors in human breastmilk: a focus on prematurity. Nutrients. 2019;11(6):1307.PubMedCentralCrossRef

Kim Y, Atalla H, Mallard B, Robert C, Karrow N. Changes in Holstein cow milk and serum proteins during intramammary infection with three different strains of Staphylococcus aureus. BMC Vet Res. 2011;7:51.PubMedPubMedCentralCrossRef

Rainard P, Riollet C, Berthon P, Cunha P, Fromageau A, Rossignol C, Gilbert FB. The chemokine CXCL3 is responsible for the constitutive chemotactic activity of bovine milk for neutrophils. Mol Immunol. 2008;45(15):4020–7.PubMedCrossRef

Stelwagen K, Carpenter E, Haigh B, Hodgkinson A, Wheeler TT. Immune components of bovine colostrum and milk. J Anim Sci. 2009;87(13 Suppl):3–9.PubMedCrossRef

Chatterton DE, Nguyen DN, Bering SB, Sangild PT. Anti-inflammatory mechanisms of bioactive milk proteins in the intestine of newborns. Int J Biochem Cell Biol. 2013;45(8):1730–47.PubMedCrossRef

Maity S, Bhat AH, Giri K, Ambatipudi K. BoMiProt: a database of bovine milk proteins. J Proteomics. 2020;215:103648.PubMedCrossRef

10.

Ramiro-Cortijo D, Singh P, Liu Y, Medina-Morales E, Yakah W, Freedman SD, Martin CR. Breast milk lipids and fatty acids in regulating neonatal intestinal development and protecting against intestinal injury. Nutrients. 2020;12(2):534.PubMedCentralCrossRef

11.

Castanys-Munoz E, Martin MJ, Prieto PA. 2’-fucosyllactose: an abundant, genetically determined soluble glycan present in human milk. Nutr Rev. 2013;71(12):773–89.PubMedCrossRef

12.

Grosvenor CE, Picciano MF, Baumrucker CR. Hormones and growth factors in milk. Endocr Rev. 1993;14(6):710–28.PubMedCrossRef

13.

Luisi S, Calonaci G, Florio P, Lombardi I, De Felice C, Bagnoli F, Petraglia F. Identification of activin A and follistatin in human milk. Growth Factors. 2002;20(3):147–50.PubMedCrossRef

14.

Panahipour L, Stahli A, Haiden N, Gruber R. TGF-beta activity in cow milk and fermented milk products: an in vitro bioassay with oral fibroblasts. Arch Oral Biol. 2018;95:15–21.PubMedCrossRef

15.

Panahipour L, Tabatabaei AA, Gruber R. Hypoallergenic infant formula lacks transforming growth factor beta activity and has a lower anti-inflammatory activity than regular infant formula. J Dairy Sci. 2020;103(8):6771–81.PubMedCrossRef

16.

Panahipour L, Husejnovic S, Nasirzade J, Semelmayer S, Gruber R. Micellar casein and whey powder hold a TGF-beta activity and regulate ID genes in vitro. Molecules 2021, 26(2).

17.

Laping NJ, Grygielko E, Mathur A, Butter S, Bomberger J, Tweed C, Martin W, Fornwald J, Lehr R, Harling J, et al. Inhibition of transforming growth factor (TGF)-beta1-induced extracellular matrix with a novel inhibitor of the TGF-beta type I receptor kinase activity: SB-431542. Mol Pharmacol. 2002;62(1):58–64.PubMedCrossRef

18.

Inman GJ, Nicolas FJ, Callahan JF, Harling JD, Gaster LM, Reith AD, Laping NJ, Hill CS. SB-431542 is a potent and specific inhibitor of transforming growth factor-beta superfamily type I activin receptor-like kinase (ALK) receptors ALK4, ALK5, and ALK7. Mol Pharmacol. 2002;62(1):65–74.PubMedCrossRef

19.

Stahli A, Bosshardt D, Sculean A, Gruber R. Emdogain-regulated gene expression in palatal fibroblasts requires TGF-betaRI kinase signaling. PLoS ONE. 2014;9(9):e105672.PubMedPubMedCentralCrossRef

20.

Strauss FJ, Stahli A, Beer L, Mitulovic G, Gilmozzi V, Haspel N, Schwab G, Gruber R. Acid bone lysate activates TGFbeta signalling in human oral fibroblasts. Sci Rep. 2018;8(1):16065.PubMedPubMedCentralCrossRef

21.

Peng J, Nemec M, Brolese E, Bosshardt DD, Schaller B, Buser D, Gruber R. Bone-conditioned medium inhibits osteogenic and adipogenic differentiation of mesenchymal cells in vitro. Clin Implant Dent Relat Res. 2015;17(5):938–49.PubMedCrossRef

22.

Di Summa F, Kargarpour Z, Nasirzade J, Stahli A, Mitulovic G, Panic-Jankovic T, Koller V, Kaltenbach C, Muller H, Panahipour L, et al. TGFbeta activity released from platelet-rich fibrin adsorbs to titanium surface and collagen membranes. Sci Rep. 2020;10(1):10203.PubMedPubMedCentralCrossRef

23.

Kargarpour Z, Nasirzade J, Panahipour L, Miron RJ, Gruber R. Liquid platelet-rich fibrin and heat-coagulated albumin gel: bioassays for TGF-beta activity. Materials (Basel). 2020;13(16):3466.CrossRef

24.

Wang Z, Gerstein M, Snyder M. RNA-Seq: a revolutionary tool for transcriptomics. Nat Rev Genet. 2009;10(1):57–63.PubMedPubMedCentralCrossRef

25.

Schafer S, Viswanathan S, Widjaja AA, Lim WW, Moreno-Moral A, DeLaughter DM, Ng B, Patone G, Chow K, Khin E, et al. IL-11 is a crucial determinant of cardiovascular fibrosis. Nature. 2017;552(7683):110–5.PubMedPubMedCentralCrossRef

26.

Widjaja AA, Singh BK, Adami E, Viswanathan S, Dong J, D’Agostino GA, Ng B, Lim WW, Tan J, Paleja BS, et al. Inhibiting interleukin 11 signaling reduces hepatocyte death and liver fibrosis, inflammation, and steatosis in mouse models of nonalcoholic steatohepatitis. Gastroenterology. 2019;157(3):777–92.PubMedCrossRef

27.

Poti F, Feuerborn R, Greco D, Battista S, Scalera E, Papotti B, Zanotti I, Nofer JR. Interleukin-11: a neglected cytokine with anti-atherogenic properties? Atherosclerosis. 2019;287(6):e283.CrossRef

28.

Gellings Lowe N, Swaney JS, Moreno KM, Sabbadini RA. Sphingosine-1-phosphate and sphingosine kinase are critical for transforming growth factor-beta-stimulated collagen production by cardiac fibroblasts. Cardiovasc Res. 2009;82(2):303–12.PubMedPubMedCentralCrossRef

29.

Panahipour L, Biasi M, Bokor TS, Thajer A, Haiden N, Gruber R. Milk lactoperoxidase decreases ID1 and ID3 expression in human oral squamous cell carcinoma cell lines. Sci Rep. 2020;10(1):5836.PubMedPubMedCentralCrossRef

30.

Jinnin M, Ihn H, Tamaki K. Characterization of SIS3, a novel specific inhibitor of Smad3, and its effect on transforming growth factor-beta1-induced extracellular matrix expression. Mol Pharmacol. 2006;69(2):597–607.PubMedCrossRef

31.

Kucich U, Rosenbloom JC, Shen G, Abrams WR, Hamilton AD, Sebti SM, Rosenbloom J. TGF-beta1 stimulation of fibronectin transcription in cultured human lung fibroblasts requires active geranylgeranyl transferase I, phosphatidylcholine-specific phospholipase C, protein kinase C-delta, and p38, but not erk1/erk2. Arch Biochem Biophys. 2000;374(2):313–24.PubMedCrossRef

32.

Halstead J, Kemp K, Ignotz RA. Evidence for involvement of phosphatidylcholine-phospholipase C and protein kinase C in transforming growth factor-beta signaling. J Biol Chem. 1995;270(23):13600–3.PubMedCrossRef

33.

Adibhatla RM, Hatcher JF, Gusain A. Tricyclodecan-9-yl-xanthogenate (D609) mechanism of actions: a mini-review of literature. Neurochem Res. 2012;37(4):671–9.PubMedCrossRef

34.

Sluzalska KD, Liebisch G, Wilhelm J, Ishaque B, Hackstein H, Schmitz G, Rickert M, Steinmeyer J. Growth factors regulate phospholipid biosynthesis in human fibroblast-like synoviocytes obtained from osteoarthritic knees. Sci Rep. 2017;7(1):13469.PubMedPubMedCentralCrossRef

35.

Stout BM, Alent BJ, Pedalino P, Holbrook R, Gluhak-Heinrich J, Cui Y, Harris MA, Gemperli AC, Cochran DL, Deas DE, et al. Enamel matrix derivative: protein components and osteoinductive properties. J Periodontol. 2014;85(2):e9–17.PubMedCrossRef

36.

Kawase T, Okuda K, Yoshie H, Burns DM. Anti-TGF-beta antibody blocks enamel matrix derivative-induced upregulation of p21WAF1/cip1 and prevents its inhibition of human oral epithelial cell proliferation. J Periodontal Res. 2002;37(4):255–62.PubMedCrossRef

37.

Gruber R, Bosshardt DD, Miron RJ, Gemperli AC, Buser D, Sculean A. Enamel matrix derivative inhibits adipocyte differentiation of 3T3-L1 cells via activation of TGF-betaRI kinase activity. PLoS ONE. 2013;8(8):e71046.PubMedPubMedCentralCrossRef

38.

Gruber R, Stahli A, Miron RJ, Bosshardt DD, Sculean A. Common target genes of palatal and gingival fibroblasts for EMD: the microarray approach. J Periodontal Res. 2015;50(1):103–12.PubMedCrossRef

39.

Sawyer JS, Anderson BD, Beight DW, Campbell RM, Jones ML, Herron DK, Lampe JW, McCowan JR, McMillen WT, Mort N, et al. Synthesis and activity of new aryl- and heteroaryl-substituted pyrazole inhibitors of the transforming growth factor-beta type I receptor kinase domain. J Med Chem. 2003;46(19):3953–6.PubMedCrossRef

40.

Ozawa T, Miyata M, Nishimura M, Ando T, Ouyang Y, Ohba T, Shimokawa N, Ohnuma Y, Katoh R, Ogawa H, et al. Transforming growth factor-beta activity in commercially available pasteurized cow milk provides protection against inflammation in mice. J Nutr. 2009;139(1):69–75.PubMedCrossRef

41.

Tremellen KP, Seamark RF, Robertson SA. Seminal transforming growth factor beta1 stimulates granulocyte-macrophage colony-stimulating factor production and inflammatory cell recruitment in the murine uterus. Biol Reprod. 1998;58(5):1217–25.PubMedCrossRef

42.

Li J, Wang J, Zou Y, Zhang Y, Long D, Lei L, Tan L, Ye R, Wang X, Zhao Z. The influence of delayed compressive stress on TGF-beta1-induced chondrogenic differentiation of rat BMSCs through Smad-dependent and Smad-independent pathways. Biomaterials. 2012;33(33):8395–405.PubMedCrossRef

43.

Huang W, Yu D, Wang M, Han Y, Lin J, Wei D, Cai J, Li B, Chen P, Zhang X. ITGBL1 promotes cell migration and invasion through stimulating the TGF-beta signalling pathway in hepatocellular carcinoma. Cell Prolif. 2020;53(7):e12836.PubMedPubMedCentralCrossRef

44.

Kutz SM, Hordines J, McKeown-Longo PJ, Higgins PJ. TGF-beta1-induced PAI-1 gene expression requires MEK activity and cell-to-substrate adhesion. J Cell Sci. 2001;114(Pt 21):3905–14.PubMedCrossRef

45.

Keating DT, Sadlier DM, Patricelli A, Smith SM, Walls D, Egan JJ, Doran PP. Microarray identifies ADAM family members as key responders to TGF-beta1 in alveolar epithelial cells. Respir Res. 2006;7:114.PubMedPubMedCentralCrossRef

46.

Zhang YE. Non-Smad pathways in TGF-beta signaling. Cell Res. 2009;19(1):128–39.PubMedCrossRef

47.

Ehrlich M, Gutman O, Knaus P, Henis YI. Oligomeric interactions of TGF-beta and BMP receptors. FEBS Lett. 2012;586(14):1885–96.PubMedCrossRef

48.

Wang J, Feng W, Li F, Shi W, Zhai C, Li S, Zhu Y, Yan X, Wang Q, Liu L, et al. SphK1/S1P mediates TGF-beta1-induced proliferation of pulmonary artery smooth muscle cells and its potential mechanisms. Pulm Circ. 2019;9(1):2045894018816977.PubMedCrossRef

Title: RNAseq of TGF-β receptor type I kinase-dependent genes in oral fibroblast exposed to milk
Authors: Layla Panahipour
Dariush Mehdipour Moghaddam
Jila Nasirzade
Zahra Kargarpour
Reinhard Gruber
Publication date: 01-12-2021
Publisher: BioMed Central
Published in: BMC Oral Health / Issue 1/2021
Electronic ISSN: 1472-6831
DOI: https://doi.org/10.1186/s12903-021-01913-5

Keynote webinar | Spotlight on medication adherence

Springer Medicine

RNAseq of TGF-β receptor type I kinase-dependent genes in oral fibroblast exposed to milk

Abstract

Background

Result

Conclusion

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Result

Conclusion

Please log in to get access to this content

Other articles of this Issue 1/2021

Preliminary feasibility torque mechanical evaluation for 3D printed orthodontic springs with different parameters: in vitro study

The effect of retrograde material type and surgical techniques on the success rate of surgical endodontic retreatment: systematic review of prospective randomized clinical trials

Prevalence of malocclusion and assessment of orthodontic treatment needs among Syrian refugee children and adolescents: a cross-sectional study

Do the dimensions of the hard palate have a relationship with the volumes of the upper airways and maxillary sinuses? A CBCT study

Effects of mouth breathing on facial skeletal development in children: a systematic review and meta-analysis

Rhamnolipid coating reduces microbial biofilm formation on titanium implants: an in vitro study