Interleukin-12 Production by Human Alveolar Macrophages Is Controlled by the Autocrine Production of Interleukin-10

217

209

A key issue for the study of tuberculosis infection (TB) is to understand why individuals infected with Mycobacterium tuberculosis experience different clinical outcomes. Elaborating the immune mechanisms that determine whether an infected individual will suffer active TB or latent infection can aid in developing treatment and prevention strategies. To better understand the dynamics of M. tuberculosis infection and immunity, we have developed a virtual human model that qualitatively and quantitatively characterizes the cellular and cytokine control network operational during TB infection. Using this model, we identify key regulatory elements in the host response. In particular, factors affecting cell functions, such as macrophage activation and bactericidal capabilities, and effector T cell functions such as cytotoxicity and cytokine production can each be determinative. The model indicates, however, that even if latency is achieved, it may come at the expense of tissue damage if the response is not properly regulated. A balance in Th1 and Th2 immune responses governed by IFN-γ, IL-10, and IL-4 facilitate this down-regulation. These results are further explored through virtual deletion and depletion experiments.

Section: Growth and Decay Rates (␣ 19 supporting

confidence: 72%

A Model to Predict Cell-Mediated Immune Regulatory Mechanisms During Human Infection withMycobacterium tuberculosis

Wigginton

Kirschner

2001

217

209

“…Nevertheless, IgA had no significant effect on MAPK activation that could underlie its inhibitory effect on IL-12. We previously showed that IgA may induce IL-10 expression in monocytes and MD-DCs (15), and IL-10 may also control IL-12 expression in an autocrine manner (16,36), as observed following IgG ligation of FcgRs. However, autocrine IL-10 was not involved in the IgA-mediated inhibition of IL-12.…”

Section: Inhibition Of Stat1 Activation By Igamentioning

confidence: 86%

FcαRI-Mediated Inhibition of IL-12 Production and Priming by IFN-γ of Human Monocytes and Dendritic Cells

Lecocq

Detry

Guisset

et al. 2013

We showed that IgA induces IL-10 in monocytes and dendritic cells. Because reciprocal inhibition exists between IL-10 and IL-12, we explored whether IgA could regulate this other immunoregulatory cytokine. In human monocytes and monocyte-derived dendritic cells preincubated with IFN-γ before stimulation by LPS, suppression of p40 and IL-12p70 production was observed upon IgA treatment during IFN-γ priming. Washout experiments and inhibition of IFN-γ–induced CXCL10 (IP-10) and FcγRI (CD64) indicated that inhibition by IgA occurred at both the LPS and IFN-γ levels. Inhibition was not affected by blockade of IL-10 or MAPK but involved FcαRI/CD89-mediated suppression of STAT1 phosphorylation. These data indicate that FcαRI ligation on human monocytes and dendritic cells inhibits IL-12 expression and type 1 activation by interfering with STAT1 activation.

“…IL-12p70, composed of p35 and p40 subunits, is a major Th1-driving cytokine establishing cell-mediated immunity (6) and preferentially expressed by APC cells such as pulmonary macrophages (21,22). We have therefore studied the relative contribution of this cytokine and its subunits in the development of a mouse model of pulmonary fibrosis induced by silica particles.…”

Section: Discussionmentioning

confidence: 99%

A Profibrotic Function of IL-12p40 in Experimental Pulmonary Fibrosis

Huaux

Arras²,

Tomasi³

et al. 2002

The p40 subunit of IL-12 (IL-12p40), but not the heterodimeric form IL-12p70, is secreted during the development of silica-induced lung fibrosis in C57BL/6 mice. To delineate the contribution of IL-12p40 to the lung inflammatory and fibrotic processes, we compared the pulmonary responses with silica particles of IL-12p35-deficient mice (IL-12p35−/−, able to produce IL-12p40) and IL-12p40-deficient mice (IL-12p40−/−). IL-12p35−/− and IL-12p40−/− animals developed strikingly contrasting responses to silica in comparison with wild-type C57BL/6 mice. Although the IL-12p40−/− mice exhibited limited inflammatory and fibrotic reactions, the IL-12p35−/− mice presented a robust and well-developed pulmonary inflammation and fibrosis. Furthermore, the silica-induced increase in lung IL-12p40 content was significantly higher in IL-12p35−/− mice than in wild-type controls, and was associated with extensive lung fibrosis and pulmonary macrophage infiltration. The contrasting responses observed between these two IL-12 subunit-deficient murine strains were not accompanied by a strict type 1 or type 2 polarization as estimated by the measurements of lung IFN-γ/IgG2a and IL-4/IgG1 content. In vitro proliferation, type I collagen expression, as well as myofibroblast differentiation of purified pulmonary fibroblasts were not affected by treatment with exogenous rIL-12p40. In vivo, supplementation with rIL-12p40 restored the impaired pulmonary fibrotic response and macrophage accumulation in silica-treated IL-12p40−/− mice, and also promoted fibrosis and macrophage influx in wild-type mice. Together, our data suggest that IL-12p40 plays an important role in silica-induced pulmonary inflammation and fibrosis, possibly by exacerbating macrophage recruitment.