Trends in Immunology
Volume 28, Issue 1, January 2007, Pages 33-38
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Review
IL-12p40: an inherently agonistic cytokine

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IL-12p40 is known as a component of the bioactive cytokines interleukin (IL)-12 and IL-23 but it is not widely recognized as having intrinsic functional activity. Recent publications have altered this perception and support an independent role for IL-12p40. IL-12p40 is induced in excess over the other subunits of IL-12 and IL-23 and can exist in a monomeric or homodimeric form. Its most widely appreciated function is to provide a negative feedback loop by competitively binding to the IL-12 receptor. However, IL-12p40 acts as a chemoattractant for macrophages and promotes the migration of bacterially stimulated dendritic cells. It is associated with several pathogenic inflammatory responses such as silicosis, graft rejection and asthma but it is also protective in a mycobacterial model. An appreciation of the independent function of IL-12p40 is important for improving our understanding of both protective and pathogenic immune responses.

Section snippets

IL-12p40, the hidden protagonist

The importance of the interleukin (IL)-12 family of cytokines in molding the effector functions of lymphocytes is well established 1, 2, 3. However, the subunit IL-12p40, which contributes to both the IL-12 and IL-23 heterodimers, is not often considered as an intrinsically functional cytokine. When it is considered, it is as an antagonist because the recombinant murine (rm)IL-12p40 homodimer (IL-12p80) competitively binds to the common receptor component IL-12Rβ1 4, 5, 6 and prevents

The IL-12 and IL-12 receptor family

IL-12p40 is produced primarily by activated inflammatory cells including macrophages, neutrophils, microglia and dendritic cells (DCs) when these cells are stimulated by a variety of pathogenic or inflammatory agents 1, 2. It can also be produced by keratinocytes [10] and airway epithelial cells [11]. IL-12p40 is a component of IL-12p70 and IL-23 (Figure 1), and both IL-12p35 [12] and IL-23p19 [13] require IL-12p40 to be secreted. However, IL-12p40 can be secreted as a monomer (IL-12p40) and as

Signaling through the IL-12 receptor family

Although IL-12Rβ2 and IL-23R have long cytoplasmic tails and mediate intracellular signaling, the IL-12Rβ1 cytoplasmic tail is short, does not contain tyrosine residues [21] (Figure 1) and has a limited signaling role [23]. In lymphocytes, the IL-12R and IL-23R complexes activate the Janus kinases Tyk2 and Jak2 and the transcription factor STAT4 [24]. Although IL-12Rβ2 and IL-23R activate Jak2 upon ligation [24], the cytoplasmic portion of IL-12Rβ1 alone can phosphorylate Tyk2 and STAT3 [25].

IL-12p40/p80 can act independently to promote cellular responses

The role of IL-12p80 as an antagonist of IL-12p70 function was first proposed by Gately and colleagues [5] and supported by the fact that exogenous rmIL-12p80 protects mice from IL-12-dependent but not TNF-dependent shock [7]. This cytokine also blocks in vivo interferon (IFN)γ production [16] and inhibits IFNγ synthesis from splenocytes treated with IL-12p70 [4]. Furthermore, in transgenic IL-12p40 mice, IFNγ is suppressed in a model of hepatic infection [34] and lupus-like autoimmune disease

What is required to confirm an independent role for IL-12p40/p80?

To determine how IL-12p40/p80 acts, we need to determine its effects on individual cells. However, there are some difficulties. Much of the early data supporting an independent role for IL-12p40 was published before the discovery of IL-23 and therefore independent roles for IL-12p40 and IL-23 were not distinguished. The differences seen between IL-12p35- and IL-12p40-deficient mice are a prime example of how IL-23 and IL-12p40/80 could both mediate non-IL-12p70 activity 42, 44. The mouse

IL-12p80 as a macrophage chemoattractant

One of the earliest established activities of IL-12p80 is as a chemoattractant for macrophages [47]. Recombinant murine IL-12p80 acts as a chemoattractant for both rat and mouse macrophages over a dose range of 10–1000 ng/ml; this activity is blocked by the anti-IL-12Rβ1 antibody and is lost following boiling [47]. Chemotactic activity is reduced when five amino acids are removed from the carboxy-terminal end of IL-12p40 [47]. In the same study, the induced expression of rIL-12p40 by a hepatoma

IL-12p80 as an inducer of DC migration

Recent work on the induction of pulmonary acquired cellular responses has identified a novel role for IL-12p40, probably in the IL-12p80 form, as an inducer of DC migration [37]. In this work the migration of DCs from the lung to the draining lymph node in response to a mycobacterial challenge is defective in mice lacking IL-12p40 but not in those lacking IL-12p35. Specifically, IL-12p40-deficient DCs are unable to migrate from the lungs to the lymph node in response to mycobacteria. The

IL-12p40/p80 can mediate inflammatory responses in the lung

An association between IL-12p40/p80 and potentially damaging inflammatory responses within the lung has been reported. Specifically, IL-12p40 and IL-12p80, as identified using western analysis, are seen at high levels in the BAL of asthma patients and are associated with macrophage accumulation [17]. Using the mouse model, it was shown that the airway epithelium expresses IL-12p40 following exposure to TNF or Sendai virus and that both IL-12p40 and IL-12p80, but little p70, are present in the

IL-12p40 in allograft rejection

IL-12p80 has been implicated in allograft rejection, in two models, because of its ability to induce IFNγ production by CD8+ T cells [58] and because macrophages accumulate in the grafted tissue [11]. In the first model, IL-12p80 acts as an agonist on CD8+ T cells, which is in contrast to its other agonist activities when it acts on macrophages and DCs. Thus, when delivered in vivo, rmIL-12p80 promotes allograft rejection [36] but, when CD8+ T cells are depleted, rmIL-12p80 promotes allograft

Concluding remarks and future perspectives

In conclusion, the ability of rmIL-12p40/p80 to promote DC migration, macrophage inflammation and the production of IFNγ in CD8+ T cells identifies this cytokine as an immunostimulatory agent (Figure 2). It is particularly timely and important that we understand this agonist activity of IL-12p40/p80 in the light of using anti-IL-12p40 antibodies to treat inflammatory diseases [60]. IL-12p80 is the primary mediator in mice and its presence in human BAL supports further searches for IL-12p80 in

Acknowledgements

We have been supported by NIH grants AI46530 and AI067723. S.A.K. was supported by a New York Community Trust–Heiser Fund fellowship. We thank John Pearl for generating Figure 1.

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