Extensive research in the past decade has identified innate immune recognition receptors and intracellular signaling pathways that culminate in inflammatory responses. Besides its role in cytoprotection, the importance of cell stress in inflammation and host defense against pathogens is emerging. Recent studies have shown that proteins in cellular stress responses, including the heat shock response, ER stress response, and DNA damage response, interact with and regulate signaling intermediates involved in the activation of innate and adaptive immune responses. The effect of such regulation by cell stress proteins may dictate the inflammatory profile of the immune response during infection and disease. In this review, we describe the regulation of innate immune cell activation by cell stress pathways, present detailed descriptions of the types of stress response proteins and their crosstalk with immune signaling intermediates that are essential in host defense, and illustrate the relevance of these interactions in diseases characteristic of aberrant immune responses, such as chronic inflammatory diseases, autoimmune disorders, and cancer. Understanding the crosstalk between cellular stress proteins and immune signaling may have translational implications for designing more effective regimens to treat immune disorders.

The immunomodulatory effects of acute and chronic alcohol use are characterized by impaired antigen-specific immune activation and by increased susceptibility to infections due to alterations in innate immune responses and inflammatory mediator production. The central feature of cellular responses to inflammatory and stress signals is the activation of the nuclear regulatory kappa B/Rel family of transcriptional factors via various surface receptor systems in immunocompetent cells. Activation of NF-kappa B, however, is regulated at multiple levels including I-kappa B degradation, nuclear translocation, and by interaction of NF-kappa B/Rel with other transcription factors. Data from our and other laboratories demonstrate that acute alcohol treatment inhibits activation and nuclear binding of the p65/p50 NF-kappa B functional heterodimer in human monocytes, a mechanism likely contributing to inhibition of pro-inflammatory cytokine production. Here we show that acute alcohol-mediated inhibition of NF-kappa B activation in various monocytic cells including human monocytes and murine macrophages. Inhibition of NF-kappa B activation by alcohol in monocytic cells was independent of I-kappa B alpha degradation. These acute-alcohol-induced changes in monocytic cells were different compared to T lymphocytes, both in Jurkat CD4 cells and peripheral human T cells, acute alcohol had a biphasic effect on TNF-alpha-induced NF-kappa B activation via an I-kappa B alpha-dependent mechanism. Inhibition of NF-kappa B activation by acute alcohol in LPS-activated human monocytes was associated with an increase in nuclear glucocorticoid receptor (GR) levels and reduced GR binding to the glucocorticoid response element (GRE). Together these findings support the hypothesis that in the presence of alcohol, nuclear interaction of NF-kappa B (p65) with glucocorticoid receptor and/or other transcription factors may contribute to the reduced NF-kappa B activation. In contrast to the inhibitory effects of acute alcohol on NF-kappa B activation in monocytic cells, chronic alcohol use and alcoholic hepatitis result in an augmentation of NF-kappa B activation and pro-inflammatory cytokine induction. These results suggest that the complex interactions of the NF-kappa B/Rel and related transcription factors including GR and heat-shock responses determine the level of activation of the immunocompetent cells in response to the challenge of acute and chronic alcohol use at the single cell level.