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


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.


Fluoroquinolone Propionic acid derivative Cytokine HL-60 



dendritic cell


extracellular signal-regulated kinase


c-Jun N-terminal kinase


Langerhans cell


mitogen-activated protein


nuclear factor kappa B


Stevens-Johnson syndrome


toxic epidermal necrolysis



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).


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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

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