Regulation and Function of the Interleukin 13 Receptor α 2 During a T Helper Cell Type 2–dominant Immune Response

Highly polarized type 2 cytokine responses can be harmful and even lethal to the host if they are too vigorous or persist too long. Therefore, it is important to elucidate the mechanisms that down-regulate these reactions. Interleukin (IL)-13 has emerged as a central mediator of T helper cell (Th)2-dominant immune responses, exhibiting a diverse array of functional activities including regulation of airway hyperreactivity, resistance to nematode parasites, and tissue remodeling and fibrosis. Here, we show that IL-13 receptor (R)α2 is a critical down-regulatory factor of IL-13–mediated tissue fibrosis induced by the parasitic helminth Schistosoma mansoni. IL-13Rα2 expression was induced after the onset of the fibrotic response, IL-10, IL-13, and Stat6 dependent, and inhibited by the Th1-inducing adjuvant IL-12. Strikingly, schistosome-infected C57BL/6 and BALB/c IL-13Rα2–deficient mice showed a marked exacerbation in hepatic fibrosis, despite displaying no change in granuloma size, tissue eosinophilia, or mastocytosis. Fibrosis increased despite the fact that IL-13 levels decreased significantly in the liver and serum. Importantly, pathology was prevented when IL-13Rα2–deficient mice were treated with a soluble IL-13Rα2-Fc construct, formally demonstrating that their exacerbated fibrotic response was due to heightened IL-13 activity. Together, these studies illustrate the central role played by the IL-13Rα2 in the down-regulation of a chronic and pathogenic Th2-mediated immune response

JNK initiates a cytokine cascade that causes Pax2 expression and closure of the optic fissure

The c-Jun NH(2)-terminal kinase (JNK) group of mitogen-activated protein kinases is stimulated in response to a wide array of cellular stresses and proinflammatory cytokines. Mice lacking individual members of the Jnk family (Jnk1, Jnk2, and Jnk3) are viable and survive without overt structural abnormalities. Here we show that mice with a compound deficiency in Jnk expression can survive to birth, but fail to close the optic fissure (retinal coloboma). We demonstrate that JNK initiates a cytokine cascade of bone morphogenetic protein-4 (BMP4) and sonic hedgehog (Shh) that induces the expression of the paired-like homeobox transcription factor Pax2 and closure of the optic fissure. Interestingly, the role of JNK to regulate BMP4 expression during optic fissure closure is conserved in Drosophila during dorsal closure, a related morphogenetic process that requires JNK-regulated expression of the BMP4 ortholog Decapentaplegic (Dpp)

An experimental model of acute and subacute viral myocarditis in the pig

AbstractTwenty-six young pigs were infected with encephalomyocarditis virus, observed clinically, studied at intervals by noninvasive and invasive methods to assess cardiac function and eventually examined pathologically.All infected animals appeared ill, usually manifesting diminished appetite, lethargy and fever. Spontaneous mortality occurred either 1 to 4 or 20 to 21 days after infection. Electrocardiographic abnormalities, seen in the majority of animals, comprised ST-T wave changes, conduction disturbances or ventricular ectopic rhythm. The majority of animals manifested echocardiographic evidence of left ventricular dilation and decreased systolic function, which improved with time in some animals.Hemodynamic studies revealed elevation of biventricular filling pressures in 3 of 10 animals; as a group, infected animals manifested significantly elevated right ventricular filling pressures. In selected animals, the feasibility of gallium scans as well as left ventriculography and coronary angiography was demonstrated.At autopsy, heart weight/body weight ratio was significantly elevated in infected animals. The heart of all but two animals showed active myocarditis associated with fibrosis and focal calcification in the later stages.In general, the cardiovascular manifestations were parallel with those seen in acute and subacute myocarditis in humans. It is concluded that encephalomyocarditis infection in the pig is a large animal model of viral myocarditis suitable for assessing alterations in the structure and function of the cardiovascular system and the effects of interventions