The subsets have different roles in the clearance of pathogens, and their unregulated activation leads to distinct immune pathologies. Th1 cells express IFN␥ and are crucial for the phagocytic immune response against intracellular pathogens, such as Mycobacterium tuberculosis, but their aberrant activation is implicated in autoimmunity (2). Human Th2 cells express IL-4, IL-5, and IL-13 and orchestrate an immune response characterized by eosinophilia and IgE class-switching to fight extracellular pathogens (2). Th2 cell activation is also central to the pathogenesis of allergic diseases, such as asthma, in which the Th2 cytokines play important roles (3-5).PMCH encodes a prohormone, pro-melanin-concentratinghormone (PMCH) of 165 aa which is proteolytically processed to form several peptides including the orexigenic peptide melanin concentrating hormone (MCH) (6). PMCH was first implicated in the regulation of appetite by the finding that the gene is up-regulated in obese, leptin-deficient mice (7). Further studies demonstrated that intracerebroventricular administration of MCH into rats increases feeding (8) and that weight gain occurs after chronic infusion of the peptide into the lateral ventricle (9), strongly suggesting that the peptide stimulates appetite. In addition, mice deficient in MCH are lean and hypophagic (10), and animals overexpressing the gene are obese (11). Several groups cloned the G protein-coupled receptor for MCH (MCHR1) (12-15), and MCHR1-deficient mice are resistant to diet-induced obesity (16,17). A second receptor, MCHR2, was later identified in humans by its homology to MCHR1 (18-23). MCHR2 is not present in the rodent genomes, but orthologs have been identified in ferret, dog and rhesus monkey, in addition to the human gene (24). PMCH therefore has an important role in increasing appetite (25), and a small molecule antagonist of MCHR1 has been shown to reduce feeding and weight gain in rats fed a high fat diet ad libitum (26).The prevalence of both asthma and obesity are increasing in the western world, and a link between the two conditions has been proposed and debated (reviewed in ref. 27). Epidemiological evidence from several studies suggests a correlation between body mass index and asthma (28-32). Using quantitative real time RT-PCR, Western blot analysis, and enzyme immunoassay, we found that activated Th2 cells selectively expressed the gene PMCH. Activated Th2 cells secreted MCH-containing proteins, and ex vivo Th2 but not Th1 cells also expressed the gene. We hypothesize that expression of PMCH by Th2 cells in vivo in the asthmatic lung may link asthma and obesity.
ResultsIn Vitro-Differentiated Th2 Cells Selectively Express PMCH. Naïve human CD4 ϩ T cells were cultured in either Th1 (IL-12 and anti-IL-4) or Th2 (IL-4 and anti-IFN␥), inducing conditions for up to 28 days with weekly restimulations (33). After differentiation the cells were highly polarized as shown by intracellular cytokine staining ( Fig. 1 A and B), with 95% of the Th1 cells producing IFN␥ on stimulation, ...