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. 2008 Jun 4;3(6):e2355.
doi: 10.1371/journal.pone.0002355.

Inhibition of p38 MAPK suppresses inflammatory cytokine induction by etoposide, 5-fluorouracil, and doxorubicin without affecting tumoricidal activity

Collin R Elsea  1 , Daniel A Roberts, Brian J Druker, Lisa J Wood
Affiliations

Inhibition of p38 MAPK suppresses inflammatory cytokine induction by etoposide, 5-fluorouracil, and doxorubicin without affecting tumoricidal activity

Collin R Elsea et al. PLoS One. .

Abstract

Cancer patients undergoing treatment with systemic cancer chemotherapy drugs often experience debilitating fatigue similar to sickness behavior, a normal response to infection or tissue damage caused by the production of the inflammatory cytokines IL-1beta, TNF-alpha, and IL-6. The p38 mitogen activated protein kinase (p38 MAPK) plays a central role in the production of these cytokines and consequently the development of sickness behavior. Targeted inhibitors of p38 MAPK can reduce systemic inflammatory cytokine production and the development of sickness behavior. Several systemic cancer chemotherapy drugs have been shown to stimulate inflammatory cytokine production, yet whether this response is related to a common ability to activate p38 MAPK is not known and is the focus of this study. This understanding may present the possibility of using p38 MAPK inhibitors to reduce chemotherapy-induced inflammatory cytokine production and consequently treatment-related fatigue. One caveat of this approach is a potential reduction in chemotherapeutic efficacy as some believe that p38 MAPK activity is required for chemotherapy-induced cytotoxicity of tumor cells. The purpose of this study was to demonstrate proof of principal that p38 MAPK inhibition can block chemotherapy-induced inflammatory cytokine production without inhibiting drug-induced cytotoxicity using murine peritoneal macrophages and Lewis Lung Carcinoma (LLC1) cells as model cell systems. Using these cells we assessed the requirement of etoposide, doxorubicin, 5-fluorouracil, and docetaxel for p38 MAPK in inflammatory cytokine production and cytotoxicity. Study findings demonstrate that clinically relevant doses of etoposide, doxorubicin, and 5-FU activated p38 MAPK in both macrophages and LLC1 cells. In contrast, docetaxel failed to activate p38 MAPK in either cell type. Activation of p38 MAPK mediated the drug's effects on inflammatory cytokine production in macrophages but not LLC1 cytotoxicity and this was confirmed with inhibitor studies.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. The induction of inflammatory cytokines by etoposide, 5-FU, doxorubicin, and docetaxel in murine macrophages in vitro is mediated by p38 MAPK.
A) Levels of phosphorylated p38 MAPK and total p38 MAPK in murine peritoneal macrophages incubated with etoposide, 5-FU, doxorubicin, and docetaxel were assessed by immunoblotting. B) Relative levels of IL-1β, TNF-α and IL-6 mRNA in etoposide, 5-FU, doxorubicin, and docetaxel-treated macrophages assessed by QRT-PCR. Fold increase in expression of each cytokine mRNA in drug-treated cells relative to carrier-treated cells is shown. C) Levels of IL-1β, TNF-α and IL-6 in the culture medium of macrophages incubated with etoposide, 5-FU, doxorubicin, and docetaxel.
Figure 2
Figure 2. The effect of p38 MAPK blockade on etoposide, 5-FU, and doxorubicin mediated induction of inflammatory cytokine production in murine macrophages.
(A) Inhibition of p38 MAPK leads to a reduction in MAPKAPK-2 phosphorylation , a downstream target of p38 MAPK. (B) The effect of pre-treatment with the p38 MAPK inhibitor on IL-1β, TNF-α and IL-6 mRNA levels. Fold increase in expression of each cytokine mRNA in drug treated cells and in cells treated with drug plus inhibitor relative to carrier treated cells is shown. (C) Levels of IL-1β, TNF-α and IL-6 in the culture supernatant of drug treated cells. A significant decrease (p<0.05) in cytokine level in cells treated with drug plus p38 MAPK inhibitor relative to cells treated with drug alone is denoted by an asterisk.
Figure 3
Figure 3. The cytotoxic effects of etoposide, 5-fluorouracil, doxorubicin, and docetaxel are not associated with p38 MAPK activation in LLC11 cells.
A) The effect of increasing concentrations of etoposide, 5-FU, doxorubicin or docetaxel on p38 MAPK activation and proliferation were assessed by immunoblotting and MTS assay respectively. B) The effect of p38 MAPK blockade on drug-induced cytotoxicity in LLC1 cells treated with etoposide, 5-FU or doxorubicin. Note that the addition of the p38 MAPK inhibitor appeared to enhance the cytotoxic effects of 5-FU on LLC1 cells (see *).
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