Innate immunity and inflammation: a transcriptional paradigm.

Hawiger J
Immunol Res. 2001 23 (2-3): 99-109

PMID: 11444396 · DOI:10.1385/IR:23:2-3:099

The innate immune response and the process of inflammation are interwoven. Excessive and continuing cytokine production in response to bacterial lipopolysacharides (LPS) or superantigens is a hallmark of the systemic inflammatory response (IR), which can be life-threatening. Dissemination of these bacterial products induces waves of proinflammatory cytokines that cause vascular injury and multiple organ dysfunction. Both LPS and superantigens induce signaling to the nucleus in mononuclear phagocytes and T cells, respectively. These signaling pathways are mediated by NF-kappaB and other stress-responsive transcription factors (SRTFs), which play a critical role in reprogramming gene expression. The nuclear import of NF-kappaB allows transcriptional activation of over 100 genes that encode mediators of inflammatory and immune responses. We have developed a novel method to block nuclear import of NF-kappaB through cell-permeable peptide transduction in monocytes, macrophages, T lymphocytes, and endothelial cells. Strikingly, a cell-permeable peptide that antagonizes nuclear import of NF-kappaB and other SRTFs, suppressed the systemic production of proinflammatory cytokines (TNFalpha and interferon gamma) in mice challenged with a lethal dose of LPS, and increased their survival by at least 90%. Thus, systemic inflammatory responses are critically dependent on the transcriptional activation ofcytokine genes that are controlled by NF-kappaB and other SRTFs.

MeSH Terms (32)

Active Transport, Cell Nucleus Animals Antigens, Bacterial Cell Nucleus Chemotaxis Cytokines DNA-Binding Proteins Endothelium, Vascular Gene Expression Regulation Humans I-kappa B Proteins Immune System Inflammation Inflammation Mediators Interferon-gamma Jurkat Cells Macromolecular Substances Mice Mice, Inbred C3H Models, Immunological NF-kappa B NF-KappaB Inhibitor alpha Peptides Phagocytes Polysaccharides, Bacterial Shock, Septic Signal Transduction Stress, Physiological Superantigens Transcription, Genetic Transcription Factors Tumor Necrosis Factor-alpha

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