Inflammatory Response Modulation by Low-Dose Anti-inflammatory Drugs Treatment in an In Vitro Osteoarthritis Cellular Model
- Authors: Iuliano M.1, Santilli V.2, Mineo A.2, Paoloni M.3, Rosa P.1, Mangino G.1, Romeo G.1
-
Affiliations:
- Department of Medico-Surgical Sciences and Biotechnologies-Polo Pontino, Faculty of Pharmacy and Medicine, Sapienza University of Rome
- Department of Anatomical and Histological Sciences, Legal Medicine and Orthopedics, Faculty of Pharmacy and Medicine, Sapienza University of Rome
- Department of Anatomical and Histological Sciences, Legal Medicine and Orthopedics, Faculty of Pharmacy and Medicine
- Issue: Vol 31, No 13 (2024)
- Pages: 1740-1753
- Section: Anti-Infectives and Infectious Diseases
- URL: https://hum-ecol.ru/0929-8673/article/view/644308
- DOI: https://doi.org/10.2174/0929867330666230407140730
- ID: 644308
Cite item
Full Text
Abstract
Background:Low-dose-medicine is based on the administration of low doses of biological regulators to restore the immunologic balance altered in the disease. Cytokines are pivotal regulators of cellular and tissue functions and impaired crosstalk, due to an imbalance between specific cytokines, it is fundamental in acute inflammation and diseases correlated to low-grade chronic inflammation. Osteoarthritis is the most prevalent arthritic disease and a leading cause of disability. In the treatment of muscle- skeletal pathologies, the therapeutic integration of conventional medicine with homotoxicology, or low-dose-medicine appears to be beneficial.
Objective:This study aims to get more insights into the role of inflammatory cytokines and chemokines during the development of osteoarthritis and to evaluate a possible blocking strategy using anti-inflammatory molecules, we resort to an in vitro experimental model using an established human chondrosarcoma cell line that underwent to a well known pro-inflammatory stimulus as bacterial lipopolysaccharide.
Methods:We tested the production of inflammatory-related cytokines and chemokines, and the efficacy of low-dose (LD) administration of anti-inflammatory compounds, namely IL-10 and anti-IL-1, to block inflammatory cellular pathways.
Results:Following an inflammatory insult, chondrocytes upregulated the expression of several pro-inflammatory cyto-/chemokines and this induction could be counteracted by LD IL-10 and anti-IL-1. We reported that these effects could be ascribed to an interfering effect of LD drugs with the NF-κB signaling.
Conclusion:Our results provided a good indication that LD drugs can be effective in inhibiting the inflammatory response in chondrocytes opening the way to new therapies for the treatment of diseases such as osteoarthritis.
About the authors
Marco Iuliano
Department of Medico-Surgical Sciences and Biotechnologies-Polo Pontino, Faculty of Pharmacy and Medicine, Sapienza University of Rome
Email: info@benthamscience.net
Valter Santilli
Department of Anatomical and Histological Sciences, Legal Medicine and Orthopedics, Faculty of Pharmacy and Medicine, Sapienza University of Rome
Email: info@benthamscience.net
Andrea Mineo
Department of Anatomical and Histological Sciences, Legal Medicine and Orthopedics, Faculty of Pharmacy and Medicine, Sapienza University of Rome
Email: info@benthamscience.net
Marco Paoloni
Department of Anatomical and Histological Sciences, Legal Medicine and Orthopedics, Faculty of Pharmacy and Medicine
Email: info@benthamscience.net
Paolo Rosa
Department of Medico-Surgical Sciences and Biotechnologies-Polo Pontino, Faculty of Pharmacy and Medicine, Sapienza University of Rome
Email: info@benthamscience.net
Giorgio Mangino
Department of Medico-Surgical Sciences and Biotechnologies-Polo Pontino, Faculty of Pharmacy and Medicine, Sapienza University of Rome
Email: info@benthamscience.net
Giovanna Romeo
Department of Medico-Surgical Sciences and Biotechnologies-Polo Pontino, Faculty of Pharmacy and Medicine, Sapienza University of Rome
Author for correspondence.
Email: info@benthamscience.net
References
- Robinson, W.H.; Lepus, C.M.; Wang, Q.; Raghu, H.; Mao, R.; Lindstrom, T.M.; Sokolove, J. Low-grade inflammation as a key mediator of the pathogenesis of osteoarthritis. Nat. Rev. Rheumatol., 2016, 12(10), 580-592. doi: 10.1038/nrrheum.2016.136 PMID: 27539668
- Mabey, T.; Honsawek, S. Cytokines as biochemical markers for knee osteoarthritis. World J. Orthop., 2015, 6(1), 95-105. doi: 10.5312/wjo.v6.i1.95 PMID: 25621214
- Kapoor, M.; Martel-Pelletier, J.; Lajeunesse, D.; Pelletier, J.P.; Fahmi, H. Role of proinflammatory cytokines in the pathophysiology of osteoarthritis. Nat. Rev. Rheumatol., 2011, 7(1), 33-42. doi: 10.1038/nrrheum.2010.196 PMID: 21119608
- Aman, Z.S.; DePhillipo, N.N.; Familiari, F.; Dickens, J.F.; LaPrade, R.F.; Dekker, T.J. Acute intervention with selective interleukin-1 inhibitor therapy may reduce the progression of posttraumatic osteoarthritis of the knee: A systematic review of current evidence. Arthroscopy, 2022, 38(8), 2543-2556. doi: 10.1016/j.arthro.2022.02.009 PMID: 35189307
- Li, M.; Li, H.; Ran, X.; Yin, H.; Luo, X.; Chen, Z. Effects of adenovirus-mediated knockdown of IRAK4 on synovitis in the osteoarthritis rabbit model. Arthritis Res. Ther., 2021, 23(1), 294. doi: 10.1186/s13075-021-02684-8 PMID: 34863246
- Paoloni, M.; Agostini, F.; Bernasconi, S.; Bona, G.; Cisari, C.; Fioranelli, M.; Invernizzi, M.; Madeo, A.; Matucci-Cerinic, M.; Migliore, A.; Quirino, N.; Ventura, C.; Viganò, R.; Bernetti, A. Information survey on the use of complementary and alternative medicine. Medicina, 2022, 58(1), 125. doi: 10.3390/medicina58010125 PMID: 35056433
- Mancini, F.; Milardi, D.; Carfagna, P.; Grande, G.; Miranda, V.; De Cicco, N.A.; Ricciardi, D.; Pontecorvi, A.; Marana, R.; De Cicco Nardone, F. Low-dose SKA progesterone and interleukin-10 modulate the inflammatory pathway in endometriotic cell lines. Int. Immunopharmacol., 2018, 55, 223-230. doi: 10.1016/j.intimp.2017.12.008 PMID: 29272819
- Castiglioni, S.; Miranda, V.; Cazzaniga, A.; Campanella, M.; Nichelatti, M.; Andena, M.; Maier, J. Femtograms of interferon-γ suffice to modulate the behavior of jurkat cells: A new light in immunomodulation. Int. J. Mol. Sci., 2017, 18(12), 2715. doi: 10.3390/ijms18122715 PMID: 29244717
- Radice, E.; Miranda, V.; Bellone, G. Low-doses of sequential-kinetic-activated interferon-γ enhance the ex vivo cytotoxicity of peripheral blood natural killer cells from patients with early-stage colorectal cancer. A preliminary study. Int. Immunopharmacol., 2014, 19(1), 66-73. doi: 10.1016/j.intimp.2013.12.011 PMID: 24369312
- Gariboldi, S.; Palazzo, M.; Zanobbio, L.; Dusio, G.F.; Mauro, V.; Solimene, U.; Cardani, D.; Mantovani, M.; Rumio, C. Low dose oral administration of cytokines for treatment of allergic asthma. Pulm. Pharmacol. Ther., 2009, 22(6), 497-510. doi: 10.1016/j.pupt.2009.05.002 PMID: 19464382
- Dugina, J.L.; Petrov, V.I.; Babayeva, A.R.; Martyushev-Poklad, A.V.; Tcherevkova, E.V.; Epstein, O.I.; Sergeeva, S.A. A randomized, open-label, comparative, 6- month trial of oral ultra-low doses of antibodies to tumor necrosis factor-alpha and diclofenac in rheumatoid arthritis. Int. J. Tissue React., 2005, 27(1), 15-21. PMID: 15847101
- Peshekhonova, L.K.; Chernov, Y.N.; Barsukova, N.A.; Peshekhonov, D.V. Clinical efficiency and tolerability of artrofoon in patients with rheumatoid arthritis associated with osteopenic syndrome. Bull. Exp. Biol. Med., 2009, 148(3), 468-469. doi: 10.1007/s10517-010-0738-1 PMID: 20396714
- Cardani, D.; Dusio, G.F.; Luchini, P.; Sciarabba, M.; Solimene, U.; Rumio, C. Oral administration of interleukin-10 and anti-il-1 antibody ameliorates experimental intestinal inflammation. Gastroenterol. Res., 2013, 6(4), 124-133. doi: 10.4021/gr556w PMID: 27785242
- Martin-Martin, L.S.; Giovannangeli, F.; Bizzi, E.; Massafra, U.; Ballanti, E.; Cassol, M.; Migliore, A. An open randomized active-controlled clinical trial with low-dose SKA cytokines versus DMARDs evaluating low disease activity maintenance in patients with rheumatoid arthritis. Drug Des. Devel. Ther., 2017, 11, 985-994. doi: 10.2147/DDDT.S118298 PMID: 28408798
- Blasi, E.; Barluzzi, R.; Bocchini, V.; Mazzolla, R.; Bistoni, F. Immortalization of murine microglial cells by a v-raf / v-myc carrying retrovirus. J. Neuroimmunol., 1990, 27(2-3), 229-237. doi: 10.1016/0165-5728(90)90073-V PMID: 2110186
- Livak, K.J.; Schmittgen, T.D. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta delta C(T)) method. Methods, 2001, 25(4), 402-408. doi: 10.1006/meth.2001.1262 PMID: 11846609
- Iuliano, M.; Mangino, G.; Chiantore, M.V.; Zangrillo, M.S.; Accardi, R.; Tommasino, M.; Fiorucci, G.; Romeo, G. Human Papillomavirus E6 and E7 oncoproteins affect the cell microenvironment by classical secretion and extracellular vesicles delivery of inflammatory mediators. Cytokine, 2018, 106, 182-189. doi: 10.1016/j.cyto.2017.11.003 PMID: 29137858
- Xie, J.; Lotoski, L.C.; Chooniedass, R.; Su, R.C.; Simons, F.E.R.; Liem, J.; Becker, A.B.; Uzonna, J.; HayGlass, K.T. Elevated antigen-driven IL-9 responses are prominent in peanut allergic humans. PLoS One, 2012, 7(10), e45377. doi: 10.1371/journal.pone.0045377 PMID: 23071516
- Boudot, A.; Kerdivel, G.; Habauzit, D.; Eeckhoute, J.; Le Dily, F.; Flouriot, G.; Samson, M.; Pakdel, F. Differential estrogen-regulation of CXCL12 chemokine receptors, CXCR4 and CXCR7, contributes to the growth effect of estrogens in breast cancer cells. PLoS One, 2011, 6(6), e20898. doi: 10.1371/journal.pone.0020898 PMID: 21695171
- Arndt, S.; Landthaler, M.; Zimmermann, J.L.; Unger, P.; Wacker, E.; Shimizu, T.; Li, Y.F.; Morfill, G.E.; Bosserhoff, A.K.; Karrer, S. Effects of cold atmospheric plasma (CAP) on ß-defensins, inflammatory cytokines, and apoptosis-related molecules in keratinocytes in vitro and in vivo. PLoS One, 2015, 10(3), e0120041. doi: 10.1371/journal.pone.0120041 PMID: 25768736
- Cho, Y.S.; Kim, K.N.; Shim, J.H. Effects of cellular 11β-hydroxysteroid dehydrogenase 1 on lps-induced inflammatory responses in synovial cell line, SW982. Immune Netw., 2017, 17(3), 171-178. doi: 10.4110/in.2017.17.3.171 PMID: 28680378
- Nennig, S.E.; Schank, J.R. The role of NFkB in drug addiction: Beyond inflammation. Alcohol Alcohol., 2017, 52(2), 172-179. doi: 10.1093/alcalc/agw098 PMID: 28043969
- Magnani, M.; Crinelli, R.; Bianchi, M.; Antonelli, A. The ubiquitin-dependent proteolytic system and other potential targets for the modulation of nuclear factor-kB (NF-kB). Curr. Drug Targets, 2000, 1(4), 387-399. doi: 10.2174/1389450003349056 PMID: 11467077
- Mangino, G.; Famiglietti, M.; Capone, C.; Veroni, C.; Percario, Z.A.; Leone, S.; Fiorucci, G.; Lülf, S.; Romeo, G.; Agresti, C.; Persichini, T.; Geyer, M.; Affabris, E. HIV-1 myristoylated nef treatment of murine microglial cells activates inducible nitric oxide synthase, NO2 production and neurotoxic activity. PLoS One, 2015, 10(6), e0130189. doi: 10.1371/journal.pone.0130189 PMID: 26066624
- Dhabhar, F.S. Effects of stress on immune function: the good, the bad, and the beautiful. Immunol. Res., 2014, 58(2-3), 193-210. doi: 10.1007/s12026-014-8517-0 PMID: 24798553
- Raphael, I.; Nalawade, S.; Eagar, T.N.; Forsthuber, T.G. T cell subsets and their signature cytokines in autoimmune and inflammatory diseases. Cytokine, 2015, 74(1), 5-17. doi: 10.1016/j.cyto.2014.09.011 PMID: 25458968
- Appay, V.; Rowland-Jones, S.L. RANTES: A versatile and controversial chemokine. Trends Immunol., 2001, 22(2), 83-87. doi: 10.1016/S1471-4906(00)01812-3 PMID: 11286708
- Daly, C.; Rollins, B.J. Monocyte chemoattractant protein-1 (CCL2) in inflammatory disease and adaptive immunity: therapeutic opportunities and controversies. Microcirculation, 2003, 10(3-4), 247-257. doi: 10.1080/mic.10.3-4.247.257 PMID: 12851642
- Iida, N.; Grotendorst, G.R. Cloning and sequencing of a new gro transcript from activated human monocytes: Expression in leukocytes and wound tissue. Mol. Cell. Biol., 1990, 10(10), 5596-5599. PMID: 2078213
- Marcu, K.B.; Otero, M.; Olivotto, E.; Borzi, R.M.; Goldring, M.B. NF-kappaB signaling: Multiple angles to target OA. Curr. Drug Targets, 2010, 11(5), 599-613. doi: 10.2174/138945010791011938 PMID: 20199390
- Bondeson, J.; Blom, A.B.; Wainwright, S.; Hughes, C.; Caterson, B.; van den Berg, W.B. The role of synovial macrophages and macrophage-produced mediators in driving inflammatory and destructive responses in osteoarthritis. Arthritis Rheum., 2010, 62(3), 647-657. doi: 10.1002/art.27290 PMID: 20187160
- Fendrick, A.M.; Greenberg, B.P. A review of the benefits and risks of nonsteroidal anti-inflammatory drugs in the management of mild-to-moderate osteoarthritis. Osteopath. Med. Prim. Care, 2009, 3(1), 1. doi: 10.1186/1750-4732-3-1 PMID: 19126235
- Liu, S.; Deng, Z.; Chen, K.; Jian, S.; Zhou, F.; Yang, Y.; Fu, Z.; Xie, H.; Xiong, J.; Zhu, W. Cartilage tissue engineering: From proinflammatory and anti-inflammatory cytokines to osteoarthritis treatments (Review). Mol. Med. Rep., 2022, 25(3), 99. doi: 10.3892/mmr.2022.12615 PMID: 35088882
- Moss, K.L.; Jiang, Z.; Dodson, M.E.; Linardi, R.L.; Haughan, J.; Gale, A.L.; Grzybowski, C.; Engiles, J.E.; Stefanovski, D.; Robinson, M.A.; Ortved, K.F. Sustained interleukin-10 transgene expression following intra-articular AAV5-IL-10 administration to horses. Hum. Gene Ther., 2020, 31(1-2), 110-118. doi: 10.1089/hum.2019.195 PMID: 31773987
- Ortved, K.F.; Begum, L.; Stefanovski, D.; Nixon, A.J. AAV-mediated overexpression of IL-10 mitigates the inflammatory cascade in stimulated equine chondrocyte pellets. Curr. Gene Ther., 2018, 18(3), 171-179. doi: 10.2174/1566523218666180510165123 PMID: 29749312
- Schulze-Tanzil, G.; Zreiqat, H.; Sabat, R.; Kohl, B.; Halder, A.; Müller, R.; John, T. Interleukin-10 and articular cartilage: Experimental therapeutical approaches in cartilage disorders. Curr. Gene Ther., 2009, 9(4), 306-315. doi: 10.2174/156652309788921044 PMID: 19534651
- Behrendt, P.; Preusse-Prange, A.; Klüter, T.; Haake, M.; Rolauffs, B.; Grodzinsky, A.J.; Lippross, S.; Kurz, B. IL-10 reduces apoptosis and extracellular matrix degradation after injurious compression of mature articular cartilage. Osteoarthritis Cartilage, 2016, 24(11), 1981-1988. doi: 10.1016/j.joca.2016.06.016 PMID: 27349464
- Reitamo, S.; Remitz, A.; Tamai, K.; Uitto, J. Interleukin-10 modulates type I collagen and matrix metalloprotease gene expression in cultured human skin fibroblasts. J. Clin. Invest., 1994, 94(6), 2489-2492. doi: 10.1172/JCI117618 PMID: 7989607
- Salaffi, F.; Ciapetti, A.; Carotti, M. The sources of pain in osteoarthritis: A pathophysiological review. Reumatismo, 2014, 66(1), 57-71. doi: 10.4081/reumatismo.2014.766 PMID: 24938198
- Kwilasz, A.J.; Grace, P.M.; Serbedzija, P.; Maier, S.F.; Watkins, L.R. The therapeutic potential of interleukin-10 in neuroimmune diseases. Neuropharmacology, 2015, 96(Pt A), 55-69. doi: 10.1016/j.neuropharm.2014.10.020
Supplementary files
