Interactions among oscillatory pathways in NF-kappa B signaling

<p>Abstract</p> <p>Background</p> <p>Sustained stimulation with tumour necrosis factor alpha (TNF-alpha) induces substantial oscillations—observed at both the single cell and population levels—in the nuclear factor kappa B (NF-kappa B) system. Although the mechanism has not yet been elucidated fully, a core system has been identified consisting of a negative feedback loop involving NF-kappa B (RelA:p50 hetero-dimer) and its inhibitor I-kappa B-alpha. Many authors have suggested that this core oscillator should couple to other oscillatory pathways.</p> <p>Results</p> <p>First we analyse single-cell data from experiments in which the NF-kappa B system is forced by short trains of strong pulses of TNF-alpha. Power spectra of the ratio of nuclear-to-cytoplasmic concentration of NF-kappa B suggest that the cells' responses are entrained by the pulsing frequency. Using a recent model of the NF-kappa B system due to Caroline Horton, we carried out extensive numerical simulations to analyze the response frequencies induced by trains of pulses of TNF-alpha stimulation having a wide range of frequencies and amplitudes. These studies suggest that for sufficiently weak stimulation, various nonlinear resonances should be observable. To explore further the possibility of probing alternative feedback mechanisms, we also coupled the model to sinusoidal signals with a wide range of strengths and frequencies. Our results show that, at least in simulation, frequencies other than those of the forcing and the main NF-kappa B oscillator can be excited via sub- and superharmonic resonance, producing quasiperiodic and even chaotic dynamics.</p> <p>Conclusions</p> <p>Our numerical results suggest that the entrainment phenomena observed in pulse-stimulated experiments is a consequence of the high intensity of the stimulation. Computational studies based on current models suggest that resonant interactions between periodic pulsatile forcing and the system's natural frequencies may become evident for sufficiently weak stimulation. Further simulations suggest that the nonlinearities of the NF-kappa B feedback oscillator mean that even sinusoidally modulated forcing can induce a rich variety of nonlinear interactions.</p

Dichloroacetate modulates cytokines toward T helper 1 function via induction of the interleukin-12&ndash;interferon-&gamma; pathway

Mujtaba M Badr,1,2 Nidal A Qinna,1,2 Fadi Qadan,2 Khalid Z Matalka1,2 1Department of Pharmacology and Biomedical Sciences, Faculty of Pharmacy and Medical Sciences, 2Petra University Pharmaceutical Center, University of Petra, Amman, Jordan Background: Dichloroacetate (DCA) is one of the new, promising anticancer drugs. DCA restores normal mitochondrial function and enables cancer cells to undergo apoptosis. In addition, DCA was found to modulate certain signaling pathways involving some transcription factors. The latter encouraged us to study DCA immunomodulatory activity on cytokines and their association with increasing DCA cancer cell cytotoxicity. Methods and results: Cell viability assay was used to determine the effect of different concentrations of DCA on the survival of 3-methylcholanthrene (MCA) fibrosarcoma cell line. DCA decreased the percent survival of MCA fibrosarcoma in a dose-dependent manner (P&lt;0.01). Furthermore, this percent survival was further reduced when MCA fibrosarcoma cells were cocultured with mouse splenocytes. The latter was observed at 10 mM DCA (P&lt;0.01), and the inhibitory concentration at 50% dropped from 23 mM to 15.6 mM DCA (P&lt;0.05). In addition, DCA significantly enhanced interferon (IFN)-&gamma; but not interleukin (IL)-17 production levels in unstimulated and stimulated mouse spleen cells. To investigate the mechanism of DCA on IFN-&gamma; production, DCA cytokine modulatory effect was tested on unstimulated macrophages, T-cells, and natural killer cells. DCA significantly increased IL-12 production from macrophages but did not modulate the production of IFN-&gamma; from either T-cells or natural killer cells. Moreover, the DCA-enhancing effect on IFN-&gamma; production was reversed by anti-IL-12 antibody. Also, the DCA cytokine modulatory effect was tested in vivo after inducing mouse skin inflammation using phorbol 12-myristate 13-acetate (PMA). DCA restored PMA-lowered IFN-&gamma; and IL-12 levels and normalized PMA-increased transforming growth factor-&szlig; level, but it inhibited IL-10 levels even further (P&lt;0.05). Conclusion: DCA has immunomodulatory activity, mainly via activation of the IL-12&ndash;IFN-&gamma; pathway and is able to modulate cytokines toward T helper 1 lymphocyte function. These DCA immunomodulatory effects are promising and further investigations are required to develop protocols for its use in cancer treatment. Keywords: dichloroacetate, fibrosarcoma, cytokines, IL-12, IFN-&gamma;, inflammatio