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Open Access Publications from the University of California

Scholarly Works (7 results)

  • Thesis
  • Peer Reviewed
UC Irvine Electronic Theses and Dissertations (2015)

Cytokines are fundamental components of the immune system and understanding their biology is a necessary step in understanding immune functions in both health and disease. Cytokines represent key mediators of the immune system which act as molecular messages that regulate both the initiation and the phenotype of the immune responses. Because of their central role in shaping immune functions, every new cytokine that has been reported has generated significant interest and has created a new field of research.

Here, I describe the identification of a novel cytokine Metrnl, which we proposed to be renamed interleukin-39 (IL-39) to reflect its association with functions of the immune system. I have explored in-depth regulation of IL-39 expression in macrophages and found that its production is regulated by multiple stimuli. Specifically, IL-39 production is highly induced by several cytokines including TNFα, IL-17, IL-12 and IL-4 whereas TGFβ and IFNƴ inhibit its production. Additionally, I have found that physiological levels of IL-39 significantly increase in response to sterile inflammation induced by thioglycollate injection. To elucidate function(s) of IL-39, I have generated a colony of IL-39-/- mice. Initial phenotyping of these mice did not reveal defects in immune cell populations in major immune compartments such as in the thymus, spleen, lymph nodes and bone marrow. Many cytokines such as IFNƴ, IL-4, TGFβ and IL-10 play a role in humoral immune responses. Therefore, I compared serum IgM, total IgG and IgA levels in IL-39 deficient and wild type mice and found that IL-39-/- mice had increased levels of IgM and decreased levels of total IgG. Among four IgG isotypes, I found significant reduction in IgG3 and IgG2b in serum of IL-39 deficient mice. Furthermore, splenocytes isolated from IL-39-/- mice produced altered levels of several cytokines and chemokines under T-cell activation conditions (with anti-CD3/anti-CD28). For example, splenocytes from IL-39 deficient mice secreted increased amount of CXCL9, CXCL10 and IL-2 while the levels of CCL3, CCL4 and IFNƴ were reduced. Because these cytokines and chemokines play important roles in protection against many pathogens, we sought to determine if IL-39 plays a role in immune response to a murine model of a T.gondii infection. Indeed, we found that IL-39-/- mice were more susceptible to the infection and displayed altered levels of several immune cell populations. This includes reduced levels of CD4+ T cells and CD8+ T cells in spleens of IL-39-/- mice when compared to WT controls. Together, these results indicate that IL-39 is a cytokine that is produced by macrophages in response to inflammation and has important functions in regulating innate and/or adaptive immune responses.

    Cover page: Functional characterization of IL-39, a novel cytokine produced by macrophages and barrier tissues.
    • Article
    • Peer Reviewed
    UC Irvine Previously Published Works (2019)
    Gut lymphocytes and the microbiota establish a reciprocal relationship that impacts the host immune response. Class I-restricted T cell-associated molecule (CRTAM) is a cell adhesion molecule expressed by intraepithelial T cells and is required for their retention in the gut. In this study, we show that CRTAM expression affects gut microbiota composition under homeostatic conditions. Moreover, Crtam-/- mice infected with the intestinal pathogen Salmonella exhibit reduced Th17 responses, lower levels of inflammation, and reduced Salmonella burden, which is accompanied by expansion of other microbial taxa. Thus, CRTAM enhances susceptibility to Salmonella, likely by promoting the inflammatory response that promotes the pathogen's growth. We also found that the gut microbiota from wild-type mice, but not from Crtam-/- mice, induces CRTAM expression and Th17 responses in ex-germ-free mice during Salmonella infection. Our study demonstrates a reciprocal relationship between CRTAM expression and the gut microbiota, which ultimately impacts the host response to enteric pathogens.
      Cover page: CRTAM Shapes the Gut Microbiota and Enhances the Severity of Infection.
      • Article
      • Peer Reviewed
      UC Irvine Previously Published Works (2018)
      We have described a novel cytokine encoded by a gene called Meteorin-like (Metrnl). Metrnl is a small (∼28 kDa) secreted protein expressed by activated macrophages and barrier tissues (mucosa and skin). Metrnl production by bone marrow macrophages is induced by several cytokines including TNF-α, IL-17α, IL-12, and IL-4 and inhibited by IFN-γ and TGF-β. Metrnl expression in macrophages is also induced by LPS, and its levels in circulation are associated with inflammatory responses in vivo. Furthermore, Metrnl regulates the production of several cytokines and chemokines in macrophages. We have produced a Metrnl-/- mouse, which is viable and shows normal development. However, it exhibits dysregulated cytokine production, alterations in IgG production, and is highly susceptible to LPS in a sepsis model. Furthermore, older Metrnl-/- mice develop inflammatory lesions, suggesting that Metrnl participates in the control of inflammatory responses. Taken together, these observations indicate that Metrnl encodes a novel immunoregulatory cytokine associated with inflammatory responses that we have designated Meteorin-β.
        Cover page: Meteorin-like/Meteorin-β Is a Novel Immunoregulatory Cytokine Associated with Inflammation
        • Article
        • Peer Reviewed
        UC Irvine Previously Published Works (2019)
        CCL28 is a mucosal chemokine that has been involved in various responses, including IgA production. We have analyzed its production in human tissues using a comprehensive microarray database. Its highest expression is in the salivary gland, indicating that it is an important component of saliva. It is also expressed in the trachea, bronchus, and in the mammary gland upon onset of lactation. We have also characterized a Ccl28-/- mouse that exhibits very low IgA levels in milk, and the IgA levels in feces are also reduced. These observations confirm a role for the CCL28/CCR10 chemokine axis in the recruitment of IgA plasmablasts to the lactating mammary gland. CCL28 is also expressed in the vomeronasal organ. We also detected olfactory defects (anosmia) in a Ccl28-/- mouse suggesting that CCL28 is involved in the function/development of olfaction. Importantly, Ccl28-/- mice are highly susceptible to Salmonella enterica serovar Typhimurium in an acute model of infection, indicating that CCL28 plays a major role in innate immunity against Salmonella in the gut. Finally, microbiome studies revealed modest differences in the gut microbiota between Ccl28-/- mice and their cohoused wild-type littermates. The latter observation suggests that under homeostatic conditions, CCL28 plays a limited role in shaping the gut microbiome.
          Cover page: CCL28 Is Involved in Mucosal IgA Responses, Olfaction, and Resistance to Enteric Infections
          • Article
          • Peer Reviewed
          UC Riverside Previously Published Works (2017)
          The hallmark of vaccines is their ability to prevent the spread of infectious pathogens and thereby serve as invaluable public health tool. Despite their medical relevance, there is a gap in our understanding of the physiological factors that mediate innate and adaptive immune response to vaccines. The endocannabinoid (eCB) system is a critical modulator of homeostasis in vertebrates. Our results indicate that macrophages and dendritic cells produce the endocannabinoid, 2-arachidonoyl-sn-glycerol (2-AG) upon antigen activation. We have also established that 2-AG levels are upregulated in the serum and in the lymph node of mice during vaccination. We hypothesized that the intrinsic release of eCBs from immune cells during activation by pathogenic antigens mitigate inflammation, but also suppress overall innate and adaptive immune response. Here we demonstrate, for the first time, that transient administration of the cannabinoid receptor 2 antagonist AM630 (10 mg/kg) or inverse agonist JTE907 (3 mg/kg) during immunization heightens the intensity and breadth of antigen-specific immune responses in young and aged mice through the upregulation of immunomodulatory genes in secondary lymphoid tissues.
            Cover page: Transient Cannabinoid Receptor 2 Blockade during Immunization Heightens Intensity and Breadth of Antigen-specific Antibody Responses in Young and Aged mice
            • Article
            • Peer Reviewed
            UC Irvine Previously Published Works (2015)
            Cytokines are involved in many functions of the immune system including initiating, amplifying and resolving immune responses. Through bioinformatics analyses of a comprehensive database of gene expression (BIGE: Body Index of Gene Expression) we observed that a small secreted protein encoded by a poorly characterized gene called meteorin-like (METRNL), is highly expressed in mucosal tissues, skin and activated macrophages. Further studies indicate that Metrnl is produced by Alternatively Activated Macrophages (AAM) and M-CSF cultured bone marrow macrophages (M2-like macrophages). In the skin, METRNL is expressed by resting fibroblasts and IFNγ-treated keratinocytes. A screen of human skin-associated diseases showed significant over-expression of METRNL in psoriasis, prurigo nodularis, actinic keratosis and atopic dermatitis. METRNL is also up-regulated in synovial membranes of human rheumatoid arthritis. Taken together, these results indicate that Metrnl represents a novel cytokine, which is likely involved in both innate and acquired immune responses.
              Cover page: METEORIN-LIKE is a cytokine associated with barrier tissues and alternatively activated macrophages
              • Article
              • Peer Reviewed
              UC San Diego Previously Published Works (2017)
              We describe a novel B cell-associated cytokine, encoded by an uncharacterized gene (C17orf99; chromosome 17 open reading frame 99), that is expressed in bone marrow and fetal liver and whose expression is also induced in peripheral B cells upon activation. C17orf99 is only present in mammalian genomes, and it encodes a small (∼27-kDa) secreted protein unrelated to other cytokine families, suggesting a function in mammalian immune responses. Accordingly, C17orf99 expression is induced in the mammary gland upon the onset of lactation, and a C17orf99-/- mouse exhibits reduced levels of IgA in the serum, gut, feces, and lactating mammary gland. C17orf99-/- mice have smaller and fewer Peyer's patches and lower numbers of IgA-secreting cells. The microbiome of C17orf99-/- mice exhibits altered composition, likely a consequence of the reduced levels of IgA in the gut. Although naive B cells can express C17orf99 upon activation, their production increases following culture with various cytokines, including IL-4 and TGF-β1, suggesting that differentiation can result in the expansion of C17orf99-producing B cells during some immune responses. Taken together, these observations indicate that C17orf99 encodes a novel B cell-associated cytokine, which we have called IL-40, that plays an important role in humoral immune responses and may also play a role in B cell development. Importantly, IL-40 is also expressed by human activated B cells and by several human B cell lymphomas. The latter observations suggest that it may play a role in the pathogenesis of certain human diseases.
                Cover page: Identification of IL-40, a Novel B Cell-Associated Cytokine.
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