Comment on Airoldi et al, page 3846

Mice genetically deficient for the IL12RB2 gene develop systemic lymphocyte activation, spontaneous autoimmunity, and malignancy, particularly plasmacytoma and lung carcinoma.

Interleukin-12 (IL-12) is a heterodimeric cytokine formed by 2 chains, IL-12 p35 or α-chain and IL-12 p40 or β-chain.1  The IL-12 p40 chain can also associate with IL-23 p19 to form the IL-23 cytokine. The IL-12 receptor is formed by 2 chains, IL-12Rβ1 and IL-12Rβ2. IL-12Rβ2 is specific for the IL-12 receptor, whereas IL-12Rβ1 also associates with IL-23R to form the receptor for IL-23. IL-12 is considered a typical proinflammatory cytokine produced mostly by myeloid cells and dendritic cells, and its biologic effects, in particular the ability to induce production of interferon γ (IFN-γ) and to support T-helper 1 (Th1) type T-cell responses, have been studied particularly on natural killer (NK) and T cells that constitutively or upon activation express functional IL-12 receptors. Although an activity of IL-12 on B-cell functions and immunoglobulin production has been described in early studies,2  whether B cells express functional IL-12 receptors has long been a controversial issue. More recently, however, it was clearly established that normal B cells express both chains of the IL-12 receptor and that they respond to IL-12 with increased immunoglobulin secretion, expression of the IL-18 receptors, and, particularly in the presence of IL-18, production of a high level of IFN-γ.3  However, Airoldi et al4  have shown that in malignant B cells the IL12RB2 gene was silenced, probably by hypermethylation. When the IL12RB2 gene expression was reestablished either by treatment of the cells with a DNA methyltransferase inhibitor or by gene transfection, IL-12, both in vitro and in vivo, induced apoptosis and growth inhibition of the malignant B cells.4 

On the basis of the data mentioned above, Airoldi et al4  have postulated that IL-12Rβ2 functions as a tumor suppressor in human B-cell malignancies. In a paper in the present issue of Blood, Airoldi and colleagues tested this hypothesis by analyzing the appearance of malignancies in aging IL12rb2–deficient mice. They observed not only a very significant incidence of plasmacytoma and lung carcinoma but also immune complex mesengial glomerulonephritis with serum antinuclear antibodies and multiorgan lymphoid infiltrates with systemic B- and T-cell activation in all aging animals. The observed autoimmune pathology may in part be secondary to an up-regulation of IL-6 in the IL12rb2–deficient animals, and the data presented suggest that there is a reciprocal down-regulation between IL-6 and IL-12. These results strongly support the conclusions that IL-12 may be important in controlling aberrant or excessive B-cell activation and that the absence of signaling of this proinflammatory cytokine paradoxically results in a state of systemic B- and T-cell activation. These findings open a new perspective on the physiologic role of IL-12. The high frequency of plasmacytoma observed in the aging IL12rb2–deficient animals may reflect either the inability of the animals to control aberrant B-cell activation or an effect of the chronic inflammatory environment on B-cell neoplastic transformation and tumor progression. The occurrence in some animals of lung adenocarcinoma may have an opposite mechanism and be linked to defective innate antitumor surveillance in the animals lacking IL-12 functions, possibly secondary to a reduced production of IFN-γ. Future studies analyzing the specific role of IL-12 in regulation of B-cell activation and transformation, autoimmunity, and solid tumor immunosurveillance will shed new light on the mechanisms of homeostatic regulation of B-cell activation and on the complex role of proinflammatory cytokines in either promoting or preventing tumor initiation and progression. ▪

Trinchieri G. Interleukin-12 and the regulation of innate resistance and adaptive immunity.
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Jelinek DF, Braaten JK. Role of IL-12 in human B lymphocyte proliferation and differentiation.
J Immunol.
Airoldi I, Gri G, Marshall JD, et al. Expression and function of IL-12 and IL-18 receptors on human tonsillar B cells.
J Immunol.
Airoldi I, Di Carlo E, Banelli B, et al. The IL-12Rbeta2 gene functions as a tumor suppressor in human B cell malignancies.
J Clin Invest.
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