Takashi Kadowaki

PI3K-mediated negative feedback regulation of IL-12 production in DCs

Although interleukin 12 (IL-12) production by dendritic cells (DCs) confers protection against harmful invasions by regulating both innate and adaptive immunity, its dysregulation may have detrimental effects on the host. We show here that phosphoinositide 3-kinase (PI3K) negatively regulates IL-12 synthesis by DCs. We found that numerous stimuli that induced IL-12 production concomitantly elicited PI3K activation in DCs, but both PI3K−/− and PI3K inhibitor–treated DCs showed increased IL-12 production. Accordingly, an enhanced T helper type 1 (TH1) response was observed upon Leishmania major infection in PI3K−/− mice. Our findings indicate that a negative feedback mechanism exists that regulates IL-12 production during DC activation and may help prevent the excessive TH1 polarization that causes undesirable immune responses.

Selective loss of gastrointestinal mast cells and impaired immunity in PI3K-deficient mice

Mice that lack the p85α regulatory subunit of phosphatidylinositol-3 kinase (PI3K) are deficient in gastrointestinal and peritoneal mast cells but have dermal mast cells. Accordingly, these mice show impaired bacterial clearance in response to acute septic peritonitis and are highly susceptible to infection by the intestinal nematode Strongyloides venezuelensis. Systemic anaphylactic shock responses, however, are intact. We found that although reconstitution of PI3K−/− mice with bone marrow–derived mast cells (BMMCs) restored anti-bacterial immunity, only T helper type 2 (TH2)-conditioned BMMCs, not standard BMMCs, were able to restore anti-nematode immunity. This finding highlights the importance of the TH2 response in the control of nematode infection. Thus, PI3K likely plays an essential role in host immune responses by regulating both the development and induction of mast cells.

Dose-Response Relationship Between Severe Hypercholesterolemia and Body Mass Index in Healthy Young Adults

To the Editor: Heterozygous familial hypercholesterolemia (FH) is a common genetic disorder associated with elevation of low-density lipoprotein cholesterol (LDL-C) and premature coronary heart disease (CHD). Familial hypercholesterolemia is underdiagnosed, partly because current diagnostic methods (eg, genetic testing) are unsuitable for population screening. TheAmericanHeart Association has provided more practical diagnostic criteria for adults: elevation of cholesterol to 190 mg/dL (5 mmol/L) or more and a family history of cholesterol levels of 190mg/dL (5mmol/L) or more or premature CHD. Moreover,