Journal
JOURNAL OF IMMUNOLOGY
Volume 186, Issue 2, Pages 1131-1139Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1002702
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Funding
- National Health and Medical Research Council (NHMRC) [356262, 356213, 461219, 508905, 637367]
- Career Development award [575531, 637374]
- Australian Research Council QEII [DP1094854]
- Victorian Cancer Agency
- Cancer Council of Victoria
- National Institutes of Health [HHSN272200700038C]
- Victorian State Government Operational Infrastructure Support grant
- NHMRC Independent Research Institutes [361646]
- Australian Research Council [DP1094854] Funding Source: Australian Research Council
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The regulation of neutrophil recruitment, activation, and disposal is pivotal for circumscribed inflammation. SHP1(Y208N/Y208N) mutant mice develop severe cutaneous inflammatory disease that is IL-1R dependent. Genetic reduction in neutrophil numbers and neutrophilic responses to infection is sufficient to prevent the spontaneous initiation of this disease. Neutrophils from SHP1(Y208N/Y208N) mice display increased pro-IL-1 beta production due to altered responses to MyD88-dependent and MyD88-independent signals. The IL-1R-dependent inflammatory disease in SHP1(Y208N/Y208N) mice develops independently of caspase 1 and proteinase 3 and neutrophil elastase. In response to Fas ligand, a caspase 1-independent inducer of IL-1 beta production, neutrophils from SHP1(Y208N/Y208N) mice produce elevated levels of IL-1 beta but display reduced caspase 3 and caspase 7 activation. In neutrophils deficient in SHP1, IL-1 beta induces high levels of pro-IL-1 beta suggesting the presence of a paracrine IL-1 beta loop. These data indicate that the neutrophil-and IL-1-dependent disease in SHP1(Y208N/Y208N) mice is a consequence of loss of negative regulation of TLR and IL-1R signaling. The Journal of Immunology, 2011, 186: 1131-1139.
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