Gastrointestinal (GI) nematode infections are an important public health and economic concern. Experimental studies have shown that resistance to infection requires CD4 ؉ T helper type 2 (Th2) cytokine responses characterized by the production of IL-4 and IL-13. However, despite >30 years of research, it is unclear how the immune system mediates the expulsion of worms from the GI tract. Here, we demonstrate that a recently described intestinal goblet cell-specific protein, RELM͞FIZZ2, is induced after exposure to three phylogenetically distinct GI nematode pathogens. Maximal expression of RELM was coincident with the production of Th2 cytokines and host protective immunity, whereas production of the Th1 cytokine, IFN-␥, inhibited RELM expression and led to chronic infection. Furthermore, whereas induction of RELM was equivalent in nematode-infected wild-type and IL-4-deficient mice, IL-4 receptor-deficient mice showed minimal RELM induction and developed persistent infections, demonstrating a direct role for IL-13 in optimal expression of RELM. Finally, we show that RELM binds to components of the nematode chemosensory apparatus and inhibits chemotaxic function of a parasitic nematode in vitro. Together, these results suggest that intestinal goblet cell-derived RELM may be a novel Th2 cytokine-induced immune-effector molecule in resistance to GI nematode infection.
Differentiation and recruitment of alternatively activated macrophages (AAMacs) are hallmarks of several inflammatory conditions associated with infection, allergy, diabetes, and cancer. AAMacs are defined by the expression of Arginase 1, chitinase-like molecules, and resistin-like molecule (RELM) α/FIZZ1; however, the influence of these molecules on the development, progression, or resolution of inflammatory diseases is unknown. We describe the generation of RELM-α–deficient (Retnla−/−) mice and use a model of T helper type 2 (Th2) cytokine-dependent lung inflammation to identify an immunoregulatory role for RELM-α. After challenge with Schistosoma mansoni (Sm) eggs, Retnla−/− mice developed exacerbated lung inflammation compared with their wild-type counterparts, characterized by excessive pulmonary vascularization, increased size of egg-induced granulomas, and elevated fibrosis. Associated with increased disease severity, Sm egg–challenged Retnla−/− mice exhibited elevated expression of pathogen-specific CD4+ T cell–derived Th2 cytokines. Consistent with immunoregulatory properties, recombinant RELM-α could bind to macrophages and effector CD4+ Th2 cells and inhibited Th2 cytokine production in a Bruton's tyrosine kinase–dependent manner. Additionally, Retnla−/− AAMacs promoted exaggerated antigen-specific Th2 cell differentiation. Collectively, these data identify a previously unrecognized role for AAMac-derived RELM-α in limiting the pathogenesis of Th2 cytokine-mediated pulmonary inflammation, in part through the regulation of CD4+ T cell responses.
Sucrase-isomaltase (SI), an intestine-specific gene, is induced in the differentiated small intestinal villous epithelium during the suckling-weaning transition in mice. We have previously identified cis-acting elements within a short evolutionarily conserved SI promoter. However, the nature and profile of expression of the interacting proteins have not been fully characterized during this developmental transition. Herein, we show that hepatocyte nuclear factor-1 alpha (HNF-1 alpha), GATA-4, and caudal related homeodomain proteins Cdx2 and Cdx1 are the primary transcription factors from the adult mouse intestinal epithelium to interact with the SIF3, GATA, and SIF1 elements of the SI promoter. We wanted to study whether HNF-1 alpha, GATA-4, and Cdx2 can cooperate in the regulation of SI gene expression. Immunolocalization experiments revealed that HNF-1 alpha is detected in rare epithelial cells of suckling mice and becomes progressively more expressed in the villous epithelial cells during the suckling-weaning transition. GATA-4 protein is expressed exclusively in villous differentiated epithelial cells of the proximal small intestine, decreases in expression in the ileum, and becomes undetectable in the colon. HNF-1 alpha, GATA-4, and Cdx2 interact in vitro and in vivo. These factors activate SI promoter activity in cotransfection experiments where GATA-4 requires the presence of both HNF-1 alpha and Cdx2. These findings imply a combinatory role of HNF-1 alpha, Cdx2, and GATA-4 for the time- and position-dependent regulation of SI transcription during development.
Niemann-Pick type C1 (NPC) disease is a lysosomal storage disease caused by mutations in the NPC1 gene, leading to an increase in unesterified cholesterol and several sphingolipids, and resulting in hepatic disease and progressive neurological disease. Whereas subcutaneous administration of the pharmaceutical excipient 2-hydroxypropyl-beta-cyclodextrin (HPβCD) ameliorated hepatic disease, doses sufficient to reduce neurological disease resulted in pulmonary toxicity. In contrast, direct administration of HPβCD into the cisterna magna of presymptomatic cats with NPC disease prevented the onset of cerebellar dysfunction for greater than a year and resulted in a reduction in Purkinje cell loss and near normal concentrations of cholesterol and sphingolipids. Moreover, administration of intracisternal HPβCD to NPC cats with ongoing cerebellar dysfunction slowed disease progression, increased survival time, and decreased the accumulation of brain gangliosides. An increase in hearing threshold was identified as a potential adverse effect. Together, these studies in the feline animal model have provided critical data on efficacy and safety of drug administration directly into the CNS that will be important for advancing HPβCD into clinical trials.
Patients with multiple endocrine neoplasia type 1 (MEN1) develop multiple endocrine tumors, primarily affecting the parathyroid, pituitary, and endocrine pancreas, due to the inactivation of the MEN1 gene. A conditional mouse model was developed to evaluate the loss of the mouse homolog, Men1, in the pancreatic beta cell. Men1 in these mice contains exons 3 to 8 flanked by loxP sites, such that, when the mice are crossed to transgenic mice expressing cre from the rat insulin promoter (RIP-cre), exons 3 to 8 are deleted in beta cells. By 60 weeks of age, >80% of mice homozygous for the floxed Men1 gene and expressing RIP-cre develop multiple pancreatic islet adenomas. The formation of adenomas results in elevated serum insulin levels and decreased blood glucose levels. The delay in tumor appearance, even with early loss of both copies of Men1, implies that additional somatic events are required for adenoma formation in beta cells. Comparative genomic hybridization of beta cell tumor DNA from these mice reveals duplication of chromosome 11, potentially revealing regions of interest with respect to tumorigenesis.Multiple endocrine neoplasia type 1 (MEN1; Online Mendelian Inheritance in Man no. 131100) is a familial tumor syndrome characterized primarily by multiple endocrine tumors of the parathyroids, anterior pituitary, and pancreas. The gene responsible for MEN1, located on chromosome 11q13 (21), was identified in 1997 by positional cloning (5), and germ line mutations in MEN1 have been found in the majority of MEN1 kindreds (1,4,27). Somatic MEN1 mutations in sporadic parathyroid adenomas, pituitary tumors, insulinomas, gastrinomas and lung carcinoids have also been reported (7,9,16,33,34). The protein product of MEN1, termed menin, is ubiquitously expressed, is targeted to the nucleus (13), and has been reported to interact with a variety of proteins, including JunD (2), Smad3 (19), Pem (22), Nm23 (25), NF-B (15), and RPA2 (32).The mouse Men1 gene has also been characterized (12, 31), and the protein product has been found to be 97% identical to human menin. As with many tumor suppressor gene knockouts, homozygous Men1 knockout mice die in utero between embryonic days 11.5 and 12.5. These mice exhibit delayed development and craniofacial abnormalities, perhaps associated with neural tube closure defects (6). This lethality has made it impossible to study the tumorigenic effects following germ line loss of both Men1 alleles. Heterozygote Men1 knockout mice develop an endocrine tumor spectrum similar to the human MEN1 phenotype, including pancreatic, pituitary, and parathyroid lesions (6).To overcome the early lethality of homozygotes and to study the function of Men1 in both the developing mouse pancreas and during tumorigenesis, we engineered specific deletion of exons 3 to 8 of the Men1 gene in the pancreatic beta cells using the cre-loxP system. Mice in which exons 3 to 8 of Men1 were flanked by loxP sites (floxed) were generated. Exons 3 to 8 were then deleted by breeding the mice with one of three independ...
During regeneration of lamprey spinal axons, growth cones lack filopodia and lamellipodia, contain little actin, and elongate much more slowly than do typical growth cones of embryonic neurons. Moreover, these regenerating growth cones are densely packed with neurofilaments (NFs). Therefore, after spinal hemisection the time course of changes in NF mRNA expression was correlated with the probability of regeneration for each of 18 identified pairs of reticulospinal neurons and 12 cytoarchitectonic groups of spinal projecting neurons. During the first 4 weeks after operation, NF message levels were reduced dramatically in all axotomized reticulospinal neurons, on the basis of semiquantitative in situ hybridization for the single lamprey NF subunit (NF-180). Thereafter, NF expression returned toward normal in neurons whose axons normally regenerate beyond the transection but remained depressed in poorly regenerating neurons. The recovery of NF expression in good regenerators was independent of axon growth across the lesion, because excision of a segment of spinal cord caudal to the transection site blocked regeneration but did not prevent the return of NF-180 mRNA. The early decrease in NF mRNA expression was not accompanied by a reduction in NF protein content. Thus the axotomy-induced loss of most of the axonal volume resulted in a reduced demand for NF rather than a reduction in volume-specific NF synthesis. We conclude that the secondary upregulation of NF message during axonal regeneration in the lamprey CNS may be part of an intrinsic growth program executed only in neurons with a strong propensity for regeneration.
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