Paradoxical Anti-Inflammatory Actions of TNF-α: Inhibition of IL-12 and IL-23 via TNF Receptor 1 in Macrophages and Dendritic Cells

Reactive arthritis (ReA) is a type of arthritis originating from certain gastrointestinal or genitourinary infections. In previous studies, we reported the development of progressive Yersinia enterocolitica-induced ReA in mice lacking TNFR p55; however, the mechanisms underlying this effect are still uncertain. In this study, we investigated the impact of TNFR p55 deficiency in modulating Ag-specific Th1 and Th17 responses during this arthritogenic process. We found more severe ReA in TNFRp55−/− mice compared with their wild-type (WT) counterparts. This effect was accompanied by increased levels of Yersinia LPS in the joints of knockout mice. Analysis of the local cytokine profile revealed greater amounts of IFN-γ and IL-17 in arthritic joints of TNFRp55−/− mice compared with WT mice at day 21 postinfection. Moreover, altered IL-17 and IFN-γ production was observed in mesenteric and inguinal lymph nodes of Yersinia-infected TNFRp55−/− mice, as well as in spleen cells obtained from infected mice and restimulated ex vivo with bacterial Ags. Increased levels of cytokine secretion were associated with a greater frequency of CD4+IL-17+, CD4+IFN-γ+, and IL-17+IFN-γ+ cells in TNFRp55−/− mice compared with WT mice. Remarkably, Ab-mediated blockade of IL-17 and/or IFN-γ resulted in reduced joint histological scores in TNFRp55−/− mice. A mechanistic analysis revealed the involvement of p40, a common subunit of heterodimeric IL-12 and IL-23, in the generation of augmented IFN-γ and IL-17 production under TNFR p55 deficiency. Taken together, these data indicate that, in the absence of TNFR p55 signaling, Th1 and Th17 effector cells may act in concert to sustain the inflammatory response in bacterial-induced arthritogenic processes.

Section: Discussionsupporting

confidence: 82%

Lack of TNFR p55 Results in Heightened Expression of IFN-γ and IL-17 during the Development of Reactive Arthritis

Eliçabe¹,

Cargnelutti²,

Serer³

et al. 2010

“…In addition to its profound proinflammatory effects, TNF was shown to limit IL-12p40 and IL-6 production in splenic APCs, suggesting a potential immunosuppressive function (22)(23)(24). We confirmed these findings and further showed that TNF expressed by both T cells and myeloid cells, rather than TNF from a single cellular source, limited in vivo production of IL-12p40 and IL-6, which regulated the development of Th1 and Th17 cells.…”

Section: Discussionsupporting

confidence: 76%

“…Increased Th cell development in vivo could be due to several factors: TNF could directly act on T cells during Th polarization or it could affect numbers, activation status, or cytokine production of APCs (22)(23)(24). First, we tested whether TNF directly affects Th cell polarization.…”

Section: Tnf Expressed By T Cells and Myeloid Cells Regulates Il-12p40mentioning

confidence: 99%

Pathogenic and Protective Functions of TNF in Neuroinflammation Are Defined by Its Expression in T Lymphocytes and Myeloid Cells

Kruglov

Lampropoulou

Fillatreau

et al. 2011

TNF displays pathogenic activities in many autoimmune disorders. However, anti-TNF therapy in multiple sclerosis patients failed because of poorly understood reasons. We used a panel of gene-targeted mice that allowed cell-type specific ablation of TNF to uncover pathogenic and protective contributions of this cytokine during autoimmune disease of the CNS. T cells and myeloid cells were found to be critical cellular sources of TNF during experimental autoimmune encephalomyelitis (EAE). TNF produced by myeloid cells accelerated the onset of disease by regulation of chemokine expression in the CNS, driving the recruitment of inflammatory cells into the target organ. TNF produced by T cells exacerbated the damage to the CNS during EAE by regulating infiltration of inflammatory myeloid cells into the CNS. In secondary lymphoid organs, TNF expressed by myeloid cells and T cells acted in synergy to dampen IL-12p40 and IL-6 production by APCs, subsequently inhibiting the development of encephalitogenic T cell responses of Th1 and Th17 types. This dual role of TNF during EAE (protective in lymphoid organs and pathogenic in CNS) suggests that global TNF blockade might be inefficient in multiple sclerosis patients because augmented autoreactive T cell development in lymphoid tissues might overwhelm the beneficial effects resulting from TNF inhibition in the CNS.

“…In this context, greater levels of TNF-␣ are produced following the use of a high effective dose of Ag relative to lower doses, in a pattern that resembles that of IFN-␥ production. TNF-␣ has been shown in multiple models to have anti-inflammatory effects via mechanisms that include apoptosis induction, IL-12/IL-23 inhibition, or CD3 down-regulation (65)(66)(67)(68)(69). However, we clearly show that reduction of elevated IFN-␥ levels is sufficient to reverse the protective effects of treatment with a high dose of Ag, placing IFN-␥ as a central regulator of the disease process.…”

Section: Discussionmentioning

confidence: 48%

Feedback Regulation of Murine Autoimmunity via Dominant Anti-Inflammatory Effects of Interferon γ

Minguela

Pastor

et al. 2007

There is a paucity of knowledge concerning the immunologic sequelae that culminate in overt autoimmunity. In the present study, we have analyzed the factors that lead to disease in the model of autoimmunity, murine experimental autoimmune encephalomyelitis (EAE). EAE in H-2u mice involves autoreactive CD4+ T cells that are induced by immunization with the immunodominant N-terminal epitope of myelin basic protein. The affinity of this epitope for I-Au can be increased by substituting lysine at position 4 with tyrosine, and this can be used to increase the effective Ag dose. Paradoxically, high doses of Ag are poorly encephalitogenic. We have used quantitative analyses to study autoreactive CD4+ T cell responses following immunization of mice with Ag doses that are at the extremes of encephalitogenicity. A dose of autoantigen that is poorly encephalitogenic results in T cell hyperresponsiveness, triggering an anti-inflammatory feedback loop in which IFN-γ plays a pivotal role. Our studies define a regulatory mechanism that serves to limit overly robust T cell responses. This feedback regulation has broad relevance to understanding the factors that determine T cell responsiveness.