Analysis of the mechanism and biological impact of p38 MAP kinase-mediated enhancement of IFN-y-induced STAT1-dependent gene expression

Living cells are exposed to a vast array of external stimuli that are translated into specific responses through the activation of intracellular signal transduction pathways. Under physiological conditions, cells encounter different stimuli at a time, causing simultaneous activation of several signaling pathways. The net outcome of such an event is usually not a simple addition of the contributions of the individual signaling pathways triggered by the specific stimuli. Due to the cross-talk between different pathways some cellular responses may become synergistically activated whereas other responses may be attenuated. Despite considerable advances in recent years, the molecular mechanisms of the links between signaling pathways are far from being explained. Activation of the p38 MAP kinase plays an important role in various processes ranging from cell growth to differentiation, to programmed cell death (apoptosis). Stimuli activating p38 are frequently accompanied by stimuli that turn on the JAK/STAT signaling pathway. The JAK/STAT signaling pathway is activated by cytokines (small secreted polypeptides) produced by cells of various origin. Activation of this pathway causes the transcription factors of the STAT family to induce expression of the specific genes. Coordinated activation of p38 by bacteria and bacteria-derived products and the JAK/STAT signaling by the cytokine interferon is critical for immune cells to successfully combat infection. We have shown that the p38 MAP kinase can increase the interferon-induced transcriptional activity of the transcription factor STAT1. The p38-mediated transcriptional enhancement was not dependent on phosphorylation of STAT1 by p38. This finding represents a novel link of how the p38 pathway influences interferon-induced signaling. It is likely that p38 is an integral part of the STAT1-containing transcriptional complexes that regulate the expression of interferon-induced genes. The presence of p38 in these complexes would restrict the activity of this enzyme to specific genes, and thereby selectively modulate their expression. The aim of the project is to analyze the molecular mechanism of the p38-mediated increase in gene transcription and to assess its physiological relevance. The results might reveal new possibilities to pharmacologically interfere with pathological processes in human diseases.

Interferons are small secreted proteins that are produced by different cells in response to bacterial or viral infections. Cells of the immune system recognize infecting microbes because the microbes carry characteristic molecules on their surface that bind to specific receptors on the surface of the immune cells. This binding initiates in the immune cell a cascade of events that lead to activation of the enzyme p38 MAP kinase and to production of interferons. Interferons and p38 MAP kinase than cooperate to achieve maximal activation of various defence mechanisms of the immune cells that in turn protect the organism against the infecting microorganisms. Our study revealed that the cooperation of p38 MAP kinase with interferons results in activation of novel interferon-induced genes. The knowledge of these genes will help uncovering new mechanisms of how interferons regulate the activity of the immune system. Surprisingly, one of these genes (with the name Tristetraprolin) possesses properties that suppress inflammation. This finding was unexpected since interferons usually activate immune responses rather than diminishing them. This result suggests that interferons can under certain circumstances reduce inflammation. This antiinflammatory property of interferons may play a fundamental role in controlling unwanted overreaction of the immune system that leads very often to serious health problems. The fact that interferons sometimes counteract inflammation has been well known for years. However, it was not clear how interferons achieve their antiinflammatory properties. Our data suggest that one way of how interferons suppress immune responses is by increasing the cellular amounts of Tristetraprolin. In our current studies we investigate whether the induction of Tristetraprolin by interferons contributes to the beneficial effects of interferons in certain diseases such as multiple sclerosis.