Identification of IL-40, a Novel B Cell–Associated Cytokine

Abstract

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.

Cytokines and Interferons: Types and Functions

“…IL-1α, IL-1β). These ILs are grouped in families based on sequence homology and receptor chain similarities or functional properties [5,44,48,49].…”

Meteorin-like/Meteorin-β Is a Novel Immunoregulatory Cytokine Associated with Inflammation

“…This screen yielded several novel secreted proteins expressed by various cells of the immune system. One of these genes ( C17ORF99 ) encodes a small secreted protein that we have recently identified as a novel B-cell associated cytokine which we have called Interleukin 40 (2). The same screen identified another gene with cytokine-like characteristics including another gene encoding a small secreted protein (~28kDa) annotated as Meteorin-like ( Metrnl ).…”

“…Metrnl −/− mice do not show metabolic abnormalities when fed either a normal or high-fat diet, further suggesting that the main functions of Metrnl are in the immune system. The last novel cytokines described include a new member of the IL-12 family that has been called IL-39 (6, 7) and our own recent description of IL-40/ C17Orf99 (2) . The name Meteorin-like only reflects its evolutionary relationship to Meteorin , but does not describe that it is a cytokine, or that it plays an important role in immunity, inflammation and likely other systems (4, 5, 8).…”

Effect of hydrogen inhalation on IL-40 and SIgA in a Rat Model of Pulmonary Mucosal Immunity

“…We speculate that the other possible mechanism SIgA enhancement is that hydrogen can activate peripheral B cells. IL-40 participates in humoral immune response, and affects the number of IgA secretory cells, resulting in an increase in IgA production (16). IL-40, however, as a newly discovered factor in the last two years, few studies…”

“…What' s more, they also found IL-40-/-mice exhibited smaller Peyer' s patches, lower numbers of IgA-secreting cells, and fewer IgA in the serum, gut, feces, and lactating mammary gland (16). Interestingly, TGF-β1 had been shown to play an important role in potentiating the expression of IL-40 by activated B cells, and a progressive increase was observed when B cells were treated with IL-4 and TGF-β1.…”