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Functional characterization of IL-39, a novel cytokine produced by macrophages and barrier tissues.

  • Author(s): Ushach, Irina
  • Advisor(s): Zlotnik, Albert
  • et al.
Abstract

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.

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