Immunosuppressive Effects of Dietary Wortmannin on Rats and Mice

Günther, Roland; Kishore, Puli Nanda; Abbas, H. K.; Mirocha, C. J.

doi:10.3109/08923978909005385

Cited by 21 publications

(8 citation statements)

References 10 publications

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“…Evaluating the pathological effects of this mycotoxin in rat models, it was found to be a potent immunosuppressor with highly toxic adverse effects. These studies long preceded its discovery as an inhibitor of PI3Ks [3,4]. Wortmannin, together with another potent pharmacological inhibitor of PI3K, LY294002, are the major pharmacological tools utilized to implicate PI3K in the regulation of granulocyte functions.…”

Section: The Pi3k Familymentioning

confidence: 99%

Regulation of granulocyte apoptosis by phosphatidylinositol 3-kinase

Lindemans

Coffer

2004

Biochemical Society Transactions

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Granulocytes are critical components of the innate immune system whose lifespan is limited by an intrinsic, constitutive, apoptotic pathway. However, the lifespan of these cells can be extended at an inflammatory locus through interaction with survival factors. Although a wide variety of factors can modulate granulocyte survival, they often utilize a common subset of intracellular signal transduction pathways. Over the last decade, evidence has accumulated that the PI3K (phosphatidylinositol 3-kinase) family of lipid kinases may be critical in regulating the ability of granulocytes to survive at inflammatory loci. Studies utilizing both pharmacological inhibitors of PI3K and isoform-specific knockout mice have demonstrated that this enzyme is needed for the anti-apoptotic effects of granulocyte survival factors. More recently, a serine/threonine protein kinase, termed protein kinase B (also known as c-akt), has been demonstrated to be important in modulating the prosurvival effects of PI3K activation. This can occur through modulation of the expression or phosphorylation of members of the Bcl-2 (B-cell lymphocytic-leukaemia proto-oncogene 2) family of apoptosis regulators. This review summarizes recent results that have implicated a role for PI3K in regulating granulocyte survival.

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Section: The Pi3k Familymentioning

confidence: 99%

Regulation of granulocyte apoptosis by phosphatidylinositol 3-kinase

Lindemans

Coffer

2004

Biochemical Society Transactions

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“…Our results show that wortmannin blocked the activation of both transcription factors by IL-1. Interestingly, wortmannin, which is a fungal metabolite, has been shown in experimental animals to exert antiinflammatory or immunosuppressive effects (24,29). It remains to be determined whether these effects can be accounted for, at least in part, by its inhibitory effects on NFB activation.…”

Section: Pi 3-kinase Is Necessary and Sufficient For Ap-1-dependent Gmentioning

confidence: 99%

Phosphatidylinositol 3-Kinase in Interleukin 1 Signaling

Reddy¹,

Huang

Liao

1997

Journal of Biological Chemistry

220

104

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The signaling mechanisms utilized by the proinflammatory cytokine interleukin-1 (IL-1) to activate the transcription factors NFB and activator protein-1 (AP-1) are poorly defined. We present evidence here that IL-1 not only stimulates a dramatic increase in phosphatidylinositol 3-kinase (PI 3-kinase) activity but also induces the physical interaction of its type I receptor with the p85 regulatory subunit of PI 3-kinase. Furthermore, two PI 3-kinase-specific inhibitors, wortmannin and a dominant-negative mutant of the p85 subunit, inhibited IL-1-induced activation of both NFB and AP-1. Transient transfection experiments indicated that whereas overexpression of PI 3-kinase may be sufficient to induce AP-1 and increase nuclear c-Fos protein levels, PI 3-kinase may need to cooperate with other IL-1-inducible signals to fully activate NFB-dependent gene expression. In this regard, cotransfection studies suggested that PI 3-kinase may functionally interact with the recently-identified IL-1-receptor-associated kinase to activate NFB. Our results thus indicate that PI 3-kinase is a novel signal transducer in IL-1 signaling and that it may differentially mediate the activation of NFB and AP-1.The biological processes of growth, differentiation, and immunity are dependent on the highly regulated action of transcription factor families such as NFB and activator protein-1 (AP-1).

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“…The first in vivo evidence for the role of PI3K in the immune system came from studies in which rats were given wortmannin, a PI3K inhibitor. These studies showed that wortmannin is a potent suppressor of immunity [40,41]. PI3K signaling is essential for the proliferation of intestinal epithelial cells.…”

Section: Pi3k/akt Signaling Pathwaymentioning

confidence: 96%

Gut Inflammation in Response to Injury: Potential Target for Therapeutic Intervention

Akhtar¹,

Choudhry²

2011

PRI

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Traumatic injuries present a major public health concern worldwide. A role of gut and/or its derived factors has been suggested in the pathogenesis associated with injury. Injury causes the activation of various signaling pathways along with the release and activation of pro-inflammatory cytokines, chemokines and adhesion molecules in the intestine. This mediates infiltration of neutrophils into the intestine. Primed and subsequently activated neutrophils release various proteolytic enzymes and superoxide anion which ultimately result in intestinal inflammation and/or injury. This review will discuss the various factors contributing to intestinal inflammation following injury. Some of the patents relevant to intestinal inflammation have also been discussed in the present manuscript.

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Immunosuppressive Effects of Dietary Wortmannin on Rats and Mice

Cited by 21 publications

References 10 publications

Regulation of granulocyte apoptosis by phosphatidylinositol 3-kinase

Regulation of granulocyte apoptosis by phosphatidylinositol 3-kinase

Phosphatidylinositol 3-Kinase in Interleukin 1 Signaling

Gut Inflammation in Response to Injury: Potential Target for Therapeutic Intervention

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