Evaluation of selected biomarkers for the detection of chemical sensitization in human skin: A comparative study applying THP-1, MUTZ-3 and primary dendritic cells in culture

Hitzler, Manuel; Bergert, Antje; Luch, Andreas; Peiser, Matthias

doi:10.1016/j.tiv.2013.04.009

Cited by 20 publications

(15 citation statements)

References 49 publications

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“…IL-8 was shown by several authors to be released from PBMDC and dendritic cell lines challenged with sensitizers (Hitzler et al 2013;Megherbi et al 2009;Mitjans et al 2008;Nukada et al 2008;Toebak et al 2006), but also keratinocyte cell lines (Mohamadzadeh et al 1994) and epidermal models (Coquette et al 2003) do release this chemokine when challenged with sensitizers. As IL-8 is well known as an attractant for neutrophils, but not directly involved in T cell-mediated immune reactions, there is a less direct mechanistic evidence for its involvement in sensitization.…”

Section: Il-8 Formationmentioning

confidence: 98%

Reporter cell lines for skin sensitization testing

Natsch

Emter

2015

Arch Toxicol

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Skin sensitization has been described as an adverse outcome pathway (AOP), comprising a number of molecular events leading to the final adverse effect. In a new paradigm of toxicology, attempts are made to collect information using single mechanistic tests addressing different targets along such an AOP and to then integrate this information to arrive at a final toxicological prediction. This proposal is strongly influenced by the availability of methods for high-throughput screening of cellular events. Reporter cell lines are a particularly useful tool in such screening paradigms, as they can deliver highly reproducible and easily measureable results, and they can be designed to quantify induction or suppression at the transcription level of very specific molecular targets within cells. The first cell-based assay for skin sensitization, which has recently received ECVAM and OECD endorsement, is the reporter cell assay KeratinoSens™, reflecting activation of the Nrf2 pathway, and other assays measuring the Nrf2 pathway are under development or validation. An alternative approach (THP-G8) was recently developed based on activation of the Interleukin-8 gene. Here, we review these assays, their role in the AOP, their mechanistic interrelationships, their use for hazard and risk assessment, and their application in integrated testing strategies. At the same time, this study reviews (1) other cellular markers for sensitizers, and the potential to develop new reporter gene assays providing additional, non-redundant information, and (2) it presents approaches and new experimental data on attempts to further improve the predictivity of the existing assay.

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Section: Il-8 Formationmentioning

confidence: 98%

Reporter cell lines for skin sensitization testing

Natsch

Emter

2015

Arch Toxicol

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“…Recently, new biomarkers for chemical sensitization have been presented, including the surface molecules PD-L1 and DCIR and the soluble factors MIP-1α, NAP-2 and IL-16 (Hitzler et al, 2013). The authors showed that monocyte-derived dendritic cells (moDCs) revealed higher expression levels of the biomarkers after stimulation with sensitizing chemicals when compared to THP-1 and MUTZ-3 cells.…”

mentioning

confidence: 99%

Myeloid human cell lines lack functional regulation of aryl hydrocarbon receptor-dependent phase I genes

Skazik-Voogt

Kühler

Ott

et al. 2015

ALTEX

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SummaryPrimary dendritic cells and myeloid cell lines are used to assess the skin sensitization hazard in in vitro approaches. The aryl hydrocarbon receptor (AhR) modulates expression of CYP enzymes, which play a significant role in the bioactivation of various xenobiotics. These studies revealed a strong constitutive expression of the AhR in primary human monocytes, monocyte-derived immature dendritic cells (iDC) and cord blood-derived Langerhans cells (LC). In contrast, mRNA and protein expression of AhR was hardly detectable in the cell lines THP-1 and MUTZ-3. U937 cells and MUTZ-3-derived dendritic (MUTZ-DC) or Langerhans cells (MUTZ-LC) showed about half the expression of AhR compared to iDC. Incubation of cells with the specific AhR-inducer benzo [a]anthracene resulted in an upregulation of CYP and IL-1β mRNA expression in primary monocytes and iDC. CYP1A1 but not CYP1B1 and IL-1β expression was increased by benzo [a]anthracene in these cell lines except for U937 cells. AhR-independent CYP genes were not regulated by benzo [a]anthracene. Constitutive mRNA expression of other non AhR-dependent CYP enzymes was higher in some of the cell lines compared to the corresponding primary cells. This study demonstrates significant differences in expression and regulation of phase I genes in cell lines currently used for in vitro skin sensitization hazard assessment compared to primary cells. Additional studies are required regarding the combination of cutaneous xenobiotic metabolizing enzymes and APC-sensitization for the development of valid in vitro models for skin sensitization assessment.

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“…The combination of IL-1α and MIP-2 (macrophage inflammatory protein-2) expression in keratinocyte cell lines can be used to measure the sensitizing potential of OECD TG429 reference compounds (Son et al, 2013). The expression of IL-8 is suggested to be an in vitro screening method for skin sensitization potential, especially in dendritic celllike THP-1 (Nukada et al, 2008;Takahashi et al, 2011;Hitzler et al, 2013). Despite the extensive efforts to validate sensitization biomarkers in epidermal cells such as keratinocytes and dendritic cell lines, more comprehensive and mechanism-based biomarkers must be identified with improved performance to predict skin sensitization potential.…”

Section: Discussionmentioning

confidence: 99%

“…We treated NHKs with the 22 reference chemicals suggested by the OECD TG429 and evaluated both cell viability and VEGF proteins that accumulated in cell culture supernatants over a 24-hour treatment period (Tables 1 and 2). In parallel, IL-8 levels were measured because IL-8 is a pivotal chemokine secreted from epidermal keratinocytes during ACD (Griffiths et al, 1991;Jia et al, 2012) and has also been suggested as a cytokine biomarker to predict sensitization potential in human keratinocyte and dendritic cell models (Hitzler et al, 2013;Son et al, 2013).…”

Section: Nhks Produce Vegf and Il-8 In Response To Pro-inflammatory Cmentioning

confidence: 99%

Chemical allergens stimulate human epidermal keratinocytes to produce lymphangiogenic vascular endothelial growth factor

Bae

Ahn

Sun

et al. 2015

Toxicology and Applied Pharmacology

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Evaluation of selected biomarkers for the detection of chemical sensitization in human skin: A comparative study applying THP-1, MUTZ-3 and primary dendritic cells in culture

Cited by 20 publications

References 49 publications

Reporter cell lines for skin sensitization testing

Reporter cell lines for skin sensitization testing

Myeloid human cell lines lack functional regulation of aryl hydrocarbon receptor-dependent phase I genes

Chemical allergens stimulate human epidermal keratinocytes to produce lymphangiogenic vascular endothelial growth factor

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