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The p38 MAPK and JNK pathways protect host cells against Clostridium perfringens beta-toxin

Masahiro Nagahama1, Masahiro Shibutani, Soshi Seike

  • 1Department of Microbiology, Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Yamashiro-cho, Tokushima, Japan.

Infection and Immunity
|July 24, 2013
PubMed

Insights

Clostridium perfringens beta-toxin causes cell death by forming pores and triggering potassium (K+) efflux. MAPK pathways, specifically p38 and JNK, are activated to promote host cell survival against this toxin.

Area of Science:

  • Microbiology
  • Cell Biology
  • Toxicology

Background:

  • Clostridium perfringens beta-toxin is a key virulence factor responsible for necrotic enteritis and enterotoxemia.
  • Beta-toxin functions as a pore-forming toxin (PFT), inducing cytotoxicity through membrane damage.
  • Mitogen-activated protein kinase (MAPK) pathways, including p38 and c-Jun N-terminal kinase (JNK), are crucial for cellular stress responses.

Purpose of the Study:

  • To investigate the role of MAPK pathways (p38 and JNK) in mediating cellular responses to Clostridium perfringens beta-toxin.
  • To characterize the mechanism of beta-toxin-induced cytotoxicity and its relationship with MAPK activation.
  • To determine the differential sensitivity of various cell lines to beta-toxin.

Main Methods:

  • Cytotoxicity assays were performed on five distinct cell lines (THP-1, U937, HL-60, BALL-1, MOLT-4) exposed to beta-toxin.
  • Beta-toxin oligomerization, membrane localization, and potassium (K+) efflux were analyzed in THP-1 cells.
  • Western blotting was used to assess the phosphorylation status of p38 MAPK and JNK.
  • Pharmacological inhibitors (SB203580 for p38, SP600125 for JNK) and specific ionic conditions (K+-free or K+-high medium) were employed to elucidate pathway involvement.

Main Results:

  • Beta-toxin induced dose- and time-dependent cytotoxicity, with varying sensitivity across cell lines (THP-1 = U937 > HL-60 > BALL-1 = MOLT-4).
  • In THP-1 cells, beta-toxin formed oligomers on lipid rafts, leading to K+ efflux.
  • Beta-toxin exposure triggered the phosphorylation of p38 MAPK and JNK.
  • Inhibition of p38 MAPK or JNK signaling exacerbated beta-toxin-induced cell death.
  • K+ depletion enhanced MAPK activation and cell death, whereas high K+ concentrations attenuated these effects.
  • Unlike streptolysin O, beta-toxin-induced p38 phosphorylation was independent of reactive oxygen species (ROS).

Conclusions:

  • Clostridium perfringens beta-toxin induces cytotoxicity via pore formation and subsequent K+ efflux.
  • The p38 MAPK and JNK pathways are activated by beta-toxin as a protective cellular response.
  • MAPK activation, independent of ROS, plays a role in host cell survival against beta-toxin.
  • Understanding these mechanisms can inform strategies against C. perfringens infections.

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