Advertisement

Cell Biology and Toxicology

, Volume 34, Issue 1, pp 65–77 | Cite as

Fluoroquinolones and propionic acid derivatives induce inflammatory responses in vitro

  • Akira NakajimaEmail author
  • Hiroki Sato
  • Shingo Oda
  • Tsuyoshi Yokoi
Original Article

Abstract

Fluoroquinolones and propionic acid derivatives are widely used antibacterials and non-steroidal anti-inflammatory drugs, respectively, which have been reported to frequently trigger drug hypersensitivity reactions. Such reactions are induced by inflammatory mediators such as cytokines and chemokines. The present study investigated whether levofloxacin, a fluoroquinolone, and loxoprofen, a propionic acid derivative, have the potential to induce immune-related gene expression in dendritic cell-like cell lines such as HL-60, K562, and THP-1, and immortalized keratinocytes such as HaCaT. The expression of IL-8, MCP-1, and TNFα messenger RNA (mRNA) was found to increase following treatment with levofloxacin or loxoprofen in HL-60 cells. In addition, these drugs increased the mRNA content of annexin A1, a factor related to keratinocyte necroptosis in patients with severe cutaneous adverse reactions. Inhibition studies using specific inhibitors of mitogen-activated protein (MAP) kinases and NF-κB suggest that the extracellular signal-regulated kinase (ERK) pathway is the pathway principally involved in the induction of cytokines and annexin A1 by levofloxacin, whereas the involvement of MAP kinases and NF-κB in the loxoprofen-induced gene expression of these factors may be limited. Fluoroquinolones and propionic acid derivatives that are structurally related to levofloxacin and loxoprofen, respectively, were also found to induce immune-related gene expression in HL-60 cells. Collectively, these results suggest that fluoroquinolones and propionic acid derivatives have the potential to induce the expression of immune-related factors and that an in vitro cell-based assay system to detect the immune-stimulating potential of systemic drugs might be useful for assessing the risk of drug hypersensitivity reactions.

Keywords

Fluoroquinolone Propionic acid derivative Cytokine HL-60 

Abbreviations

DC

dendritic cell

ERK

extracellular signal-regulated kinase

JNK

c-Jun N-terminal kinase

LC

Langerhans cell

MAP

mitogen-activated protein

NF-κB

nuclear factor kappa B

SJS

Stevens-Johnson syndrome

TEN

toxic epidermal necrolysis

Notes

Acknowledgements

This study was supported in part by Grants-in-Aid for Challenging Exploratory Research no. 24659073 from the Japan Society for the Promotion of Science.

Supplementary material

10565_2017_9391_MOESM1_ESM.pdf (43 kb)
ESM 1 Determination of drug concentrations that produce less than 30% loss of cell viability in HL-60 cells. HL-60 cells were treated with various concentrations of drugs for 24 h, and the cell viability was evaluated via Cell Counting Kit-8 assay. Data are shown as the mean ± SD (n = 3). (PDF 43.3 kb).
10565_2017_9391_MOESM2_ESM.pdf (34 kb)
ESM 2 The ATF4 mRNA levels after treatment with levofloxacin and loxoprofen in HL-60 cells. Cells were stimulated with levofloxacin (1480 μM) or loxoprofen (2910 μM) for the indicated durations. The mRNA levels of ATF4 were analyzed with real-time RT-PCR. Data are shown as the mean ± SD (n = 3). (PDF 33.6 kb).
10565_2017_9391_MOESM3_ESM.pdf (49 kb)
ESM 3 The ATF4 protein levels after treatment with levofloxacin and loxoprofen in HL-60 cells. (A) Levofloxacin. (B) Loxoprofen. Cells were stimulated with levofloxacin (1480 μM) or loxoprofen (2910 μM) for 24 h. The ATF4 and GAPDH protein levels were analyzed with immunoblot analysis. (PDF 49.4 kb).
10565_2017_9391_MOESM4_ESM.pdf (16 kb)
ESM 4 (PDF 16.2 kb).
10565_2017_9391_MOESM5_ESM.pdf (16 kb)
ESM 5 (PDF 15.6 kb).
10565_2017_9391_MOESM6_ESM.pdf (30 kb)
ESM 6 (PDF 30.2 kb).

References

  1. Abe J, Umetsu R, Mataki K, Kato Y, Ueda N, Nakayama Y, et al. Analysis of Stevens-Johnson syndrome and toxic epidermal necrolysis using the Japanese Adverse Drug Event Report database. J Pharm Health Care Sci. 2016;2:14.CrossRefPubMedPubMedCentralGoogle Scholar
  2. Bellón T, Blanca M. The innate immune system in delayed cutaneous allergic reactions to medications. Curr Opin Allergy Clin Immunol. 2011;11:292–8.CrossRefPubMedGoogle Scholar
  3. Berthier-Vergnes O, Bermond F, Flacher V, Massacrier C, Schmitt D, Péguet-Navarro J. TNF-alpha enhances phenotypic and functional maturation of human epidermal Langerhans cells and induces IL-12 p40 and IP-10/CXCL-10 production. FEBS Lett. 2005;579:3660–8.CrossRefPubMedGoogle Scholar
  4. Blanca-López N, Barrionuevo E, Andreu I, Canto MG. Hypersensitivity reactions to nonsteroidal anti-inflammatory drugs: from phenotyping to genotyping. Curr Opin Allergy Clin Immunol. 2014;14:271–7.CrossRefPubMedGoogle Scholar
  5. Blázquez AB, Cuesta J, Mayorga C. Role of dendritic cells in drug allergy. Curr Opin Allergy Clin Immunol. 2011;11:279–84.CrossRefPubMedGoogle Scholar
  6. Choo KS, Kim IW, Jung JK, Suh YG, Chung SJ, Lee MH, et al. Simultaneous determination of loxoprofen and its diastereomeric alcohol metabolites in human plasma and urine by a simple HPLC-UV detection method. J Pharm Biomed Anal. 2001;25:639–50.CrossRefPubMedGoogle Scholar
  7. Davila G, Ruiz-Hornillos J, Rojas P, De Castro F, Zubeldia JM. Toxic epidermal necrolysis induced by levofloxacin. Ann Allergy Asthma Immunol. 2009;102:441–2.CrossRefPubMedGoogle Scholar
  8. Day RO, Graham GG, Hicks M, McLachlan AJ, Stocker SL, Williams KM. Clinical pharmacokinetics and pharmacodynamics of allopurinol and oxypurinol. Clin Pharmacokinet. 2007;46:623–44.CrossRefPubMedGoogle Scholar
  9. Demoly P, Adkinson NF, Brockow K, Castells M, Chiriac AM, Greenberger PA, et al. International consensus on drug allergy. Allergy. 2014;69:420–37.CrossRefPubMedGoogle Scholar
  10. Fujimura A, Kajiyama H, Kumagai Y, Nakashima H, Sugimoto K, Ebihara A. Chronopharmacokinetic studies of pranoprofen and procainamide. J Clin Pharmacol. 1989;29:786–90.CrossRefPubMedGoogle Scholar
  11. Gavins FN, Hickey MJ. Annexin A1 and the regulation of innate and adaptive immunity. Front Immunol. 2012;3:354.CrossRefPubMedPubMedCentralGoogle Scholar
  12. Gonçalo M, Martins J, Silva A, Neves B, Figueiredo A, Cruz T, et al. Systemic drugs inducing non-immediate cutaneous adverse reactions and contact sensitizers evoke similar responses in THP-1 cells. J Appl Toxicol. 2015;35:398–406.CrossRefPubMedGoogle Scholar
  13. Gustafsson F, Foster AJ, Sarda S, Bridgland-Taylor MH, Kenna JG. A correlation between the in vitro drug toxicity of drugs to cell lines that express human P450s and their propensity to cause liver injury in humans. Toxicol Sci. 2014;137:189–211.CrossRefPubMedGoogle Scholar
  14. Huggins A, Paschalidis N, Flower RJ, Perretti M, D'Acquisto F. Annexin-1-deficient dendritic cells acquire a mature phenotype during differentiation. FASEB J. 2009;23:985–96.CrossRefPubMedGoogle Scholar
  15. Kaniwa N, Ueta M, Nakamura R, Okamoto-Uchida Y, Sugiyama E, Maekawa K, et al. Drugs causing severe ocular surface involvements in Japanese patients with Stevens-Johnson syndrome/toxic epidermal necrolysis. Allergol Int. 2015;64:379–81.CrossRefPubMedGoogle Scholar
  16. Kobayashi T, Homma M, Momo K, Kobayashi D, Kohda Y. A simple chromatographic method for determining norfloxacin and enoxacin in pharmacokinetic study assessing CYP1A2 inhibition. Biomed Chromatogr. 2011;25:435–8.CrossRefPubMedGoogle Scholar
  17. Laemmli UK. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature. 1970;227:680–5.CrossRefPubMedGoogle Scholar
  18. Lapi F, Tuccori M, Motola D, Pugi A, Vietri M, Montanaro N, et al. Safety profile of the fluoroquinolones: analysis of adverse drug reactions in relation to prescription data using four regional pharmacovigilance databases in Italy. Drug Saf. 2010;33:789–99.CrossRefPubMedGoogle Scholar
  19. Leone R, Venegoni M, Motola D, Moretti U, Piazzetta V, Cocci A, et al. Adverse drug reactions related to the use of fluoroquinolone antimicrobials: an analysis of spontaneous reports and fluoroquinolone consumption data from three Italian regions. Drug Saf. 2003;26:109–20.CrossRefPubMedGoogle Scholar
  20. Liu HH. Safety profile of the fluoroquinolones: focus on levofloxacin. Drug Saf. 2010;33:353–69.CrossRefPubMedGoogle Scholar
  21. Lode H. Evidence of different profiles of side effects and drug-drug interactions among the quinolones—the pharmacokinetic standpoint. Chemotherapy. 2001;47(Suppl 3):24–31.CrossRefPubMedGoogle Scholar
  22. Lopez S, Gomez E, Torres MJ, Pozo D, Fernandez TD, Ariza A, et al. Betalactam antibiotics affect human dendritic cells maturation through MAPK/NF-kB systems. Role in allergic reactions to drugs. Toxicol Appl Pharmacol. 2015;288:289–99.CrossRefPubMedGoogle Scholar
  23. Luís A, Martins JD, Silva A, Ferreira I, Cruz MT, Neves BM. Oxidative stress-dependent activation of the eIF2α–ATF4 unfolded protein response branch by skin sensitizer 1-fluoro-2,4-dinitrobenzene modulates dendritic-like cell maturation and inflammatory status in a biphasic manner. Free Radic Biol Med. 2014;77:217–29.CrossRefPubMedGoogle Scholar
  24. Mizuno K, Toyoda Y, Fukami T, Nakajima M, Yokoi T. Stimulation of pro-inflammatory responses by mebendazole in human monocytic THP-1 cells through an ERK signaling pathway. Arch Toxicol. 2011;85:199–207.CrossRefPubMedGoogle Scholar
  25. Nakahara T, Moroi Y, Uchi H, Furue M. Differential role of MAPK signaling in human dendritic cell maturation and Th1/Th2 engagement. J Dermatol Sci. 2006;42:1–11.CrossRefPubMedGoogle Scholar
  26. Nakajima A, Oda S, Yokoi T. Allopurinol induces innate immune responses through mitogen-activated protein kinase signaling pathways in HL-60 cells. J Appl Toxicol. 2016;36:1120–8.CrossRefPubMedGoogle Scholar
  27. Ouwehand K, Scheper RJ, de Gruijl TD, Gibbs S. Epidermis-to-dermis migration of immature Langerhans cells upon topical irritant exposure is dependent on CCL2 and CCL5. Eur J Immunol. 2010;40:2026–34.CrossRefPubMedGoogle Scholar
  28. Pan K, Wang H, Liu WL, Zhang HK, Zhou J, Li JJ, et al. The pivotal role of p38 and NF-kappaB signal pathways in the maturation of human monocyte-derived dendritic cells stimulated by streptococcal agent OK-432. Immunobiology. 2009;214:350–8.CrossRefPubMedGoogle Scholar
  29. Pirmohamed M, Naisbitt DJ, Gordon F, Park BK. The danger hypothesis—potential role in idiosyncratic drug reactions. Toxicology. 2002;181-182:55–63.CrossRefPubMedGoogle Scholar
  30. Ramasamy SN, Korb-Wells CS, Kannangara DR, Smith MW, Wang N, et al. Allopurinol hypersensitivity: a systematic review of all published cases, 1950–2012. Drug Saf. 2013;36:953–80.CrossRefPubMedGoogle Scholar
  31. Roujeau JC, Stern RS. Severe adverse cutaneous reactions to drugs. N Engl J Med. 1994;331:1272–85.CrossRefPubMedGoogle Scholar
  32. Roychowdhury S, Svensson CK. Mechanisms of drug-induced delayed-type hypersensitivity reactions in the skin. AAPS J. 2005;7:E834–46.CrossRefPubMedPubMedCentralGoogle Scholar
  33. Sachs B, Fischer-Barth W, Merk HF. Reporting rates for severe hypersensitivity reactions associated with prescription-only drugs in outpatient treatment in Germany. Pharmacoepidemiol Drug Saf. 2015;24:1076–84.CrossRefPubMedGoogle Scholar
  34. Saito N, Qiao H, Yanagi T, Shinkuma S, Nishimura K, Suto A, et al. An annexin A1-FPR1 interaction contributes to necroptosis of keratinocytes in severe cutaneous adverse drug reactions. Sci Transl Med. 2014;6:245ra95.CrossRefPubMedGoogle Scholar
  35. Sánchez-Borges M, Capriles-Hulett A, Caballero-Fonseca F. Risk of skin reactions when using ibuprofen-based medicines. Expert Opin Drug Saf. 2005;4:837–48.CrossRefPubMedGoogle Scholar
  36. Schmid DA, Campi P, Pichler WJ. Hypersensitivity reactions to quinolones. Curr Pharm Des. 2006;12:3313–26.CrossRefPubMedGoogle Scholar
  37. Sebastian K, Ott H, Zwadlo-Klarwasser G, Skazik-Voogt C, Marquardt Y, Czaja K, et al. Evaluation of the sensitizing potential of antibiotics in vitro using the human cell lines THP-1 and MUTZ-LC and primary monocyte-derived dendritic cells. Toxicol Appl Pharmacol. 2012;262:283–92.CrossRefPubMedGoogle Scholar
  38. Sharma AM, Uetrecht J. Bioactivation of drugs in the skin: relationship to cutaneous adverse drug reactions. Drug Metab Rev. 2014;46:1–18.CrossRefPubMedGoogle Scholar
  39. Williams RL, Upton RA. The clinical pharmacology of ketoprofen. J Clin Pharmacol. 1988;28:S13–22.CrossRefPubMedGoogle Scholar
  40. Xu JJ, Henstock PV, Dunn MC, Smith AR, Chabot JR, de Graaf D. Cellular imaging predictions of clinical drug-induced liver injury. Toxicol Sci. 2008;105:97–105.CrossRefPubMedGoogle Scholar
  41. Yamazaki S, Yokozeki H, Satoh T, Katayama I, Nishioka K. TNF-alpha, RANTES, and MCP-1 are major chemoattractants of murine Langerhans cells to the regional lymph nodes. Exp Dermatol. 1998;7:35–41.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2017

Authors and Affiliations

  • Akira Nakajima
    • 1
    Email author
  • Hiroki Sato
    • 1
  • Shingo Oda
    • 1
  • Tsuyoshi Yokoi
    • 1
  1. 1.Department of Drug Safety Sciences, Division of Clinical PharmacologyNagoya University Graduate School of MedicineNagoyaJapan

Personalised recommendations