Interleukin-11 therapy selectively downregulates type I cytokine proinflammatory pathways in psoriasis lesions

Trepicchio, William L.; Ozawa, Masashi; Walters, Ian; Kikuchi, Toyoko; Gilleaudeau, Patricia; Bliss, Judith L.; Schwertschlag, Ullrich; Dorner, Andrew J.; Krueger, James G.

doi:10.1172/jci6910

Cited by 204 publications

(185 citation statements)

References 46 publications

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“…Because our study has only a limited number of patients, and TNF-␣ mRNA and protein processing is quite complicated, a more highly powered study specifically designed to address TNF-␣ levels and clinical improvement will be necessary to validate these observations. Among new antipsoriatic reagents, anti-IL-12p40 therapy achieved high efficacy according to the data we currently have (7,21,22,45,47,48). Our findings in this study have revealed the mechanism of action for anti-IL-12p40 therapy.…”

Section: Discussionsupporting

confidence: 53%

“…Therefore, it is unlikely that reduced IFN-␥ mRNA levels are due to decreased infiltration of T cells at this early time point. It has been reported that psoriatic lesions, which improved by other treatments, began to show large and significant decreases in epidermal thickness and lesional T cells and DCs at 4 -6 wk after treatment (47)(48)(49). Therefore, we presume that all of these markers of histologic changes become more evident at time points later than 2 wk.…”

Section: Discussionmentioning

confidence: 69%

“…been reported that TNF-␣ mRNA levels were higher in psoriatic lesions compared with nonlesional skin and they decreased in responders after treatment (47). Because the origin of TNF-␣ is not only Th1 cells, the production of TNF-␣ is not necessarily IL-12/ IL-23 dependent.…”

Section: Discussionmentioning

confidence: 96%

“…Total CD11c ϩ cells decreased at 2 wk, but the decrease was not statistically significant in both responder groups (Table I). It has been reported that the elevated mRNA level of T cell markers correlates with increased numbers of T cells in psoriatic lesions as measured by histologic analysis (47). CD2 mRNA levels of even high responders changed a little; ϩ16.0 Ϯ 10.6% at 48 h and Ϫ15.9 Ϯ 6.4% at 2 wk.…”

Section: Immunohistochemical Analysis Of Lesional T Cells and Dcs Folmentioning

confidence: 96%

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An Anti-IL-12p40 Antibody Down-Regulates Type 1 Cytokines, Chemokines, and IL-12/IL-23 in Psoriasis

Toichi

Torres

McCormick

et al. 2006

The Journal of Immunology

188

126

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Psoriasis is characterized by activation of T cells with a type 1 cytokine profile. IL-12 and IL-23 produced by APCs are essential for inducing Th1 effector cells. Promising clinical results of administration of an Ab specific for the p40 subunit of IL-12 and IL-23 (anti-IL-12p40) have been reported recently. This study evaluated histological changes and mRNA expression of relevant cytokines and chemokines in psoriatic skin lesions following a single administration of anti-IL-12p40, using immunohistochemistry and real-time RT-PCR. Expression levels of type 1 cytokine (IFN-γ) and chemokines (IL-8, IFN-γ-inducible protein-10, and MCP-1) were significantly reduced at 2 wk posttreatment. The rapid decrease of these expression levels preceded clinical response and histologic changes. Interestingly, the level of an anti-inflammatory cytokine, IL-10, was also significantly reduced. Significant reductions in TNF-α levels and infiltrating T cells were observed in high responders (improvement in clinical score, ≥75% at 16 wk), but not in low responders. Of importance, the levels of APC cytokines, IL-12p40 and IL-23p19, were significantly decreased in both responder populations, with larger decreases in high responders. In addition, baseline levels of TNF-α significantly correlated with the clinical improvement at 16 wk, suggesting that these levels may predict therapeutic responsiveness to anti-IL-12p40. Thus, in a human Th1-mediated disease, blockade of APC cytokines by anti-IL-12p40 down-regulates expression of type 1 cytokines and chemokines that are downstream of IL-12/IL-23, and also IL-12/IL-23 themselves, with a pattern indicative of coordinated deactivation of APCs and Th1 cells.

show abstract

Section: Discussionsupporting

confidence: 53%

Section: Discussionmentioning

confidence: 69%

Section: Discussionmentioning

confidence: 96%

Section: Immunohistochemical Analysis Of Lesional T Cells and Dcs Folmentioning

confidence: 96%

See 2 more Smart Citations

An Anti-IL-12p40 Antibody Down-Regulates Type 1 Cytokines, Chemokines, and IL-12/IL-23 in Psoriasis

Toichi

Torres

McCormick

et al. 2006

The Journal of Immunology

188

126

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“…IL-6 also induces the expression of multiple factors with anti-inflammatory properties, including IL-1R antagonist, soluble TNF receptors, IL-10, acute phase reactants, glucocorticoids, protease inhibitors (such as tissue inhibitor of metalloproteinase-1), and suppressors of cytokine signaling (SOCS) 3 proteins (12, 14 -20). Consistent with these anti-inflammatory effects, IL-6 has been shown to attenuate inflammatory lung disease (21) and to play a chondroprotective role in zymosan-induced arthritis (22), and IL-11 is an effective anti-inflammatory agent in collagen-induced arthritis (23) and psoriasis (24). These observations suggest that induction of IL-6 and IL-11 expression during inflammation, similar to induction of IL-10, may contribute to a negative feedback loop.…”

mentioning

confidence: 85%

Inhibition of IL-6 and IL-10 Signaling and Stat Activation by Inflammatory and Stress Pathways

Ahmed¹,

Ivashkiv

2000

The Journal of Immunology

120

110

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The development and resolution of an inflammatory process are regulated by a complex interplay among cytokines that have pro- and anti-inflammatory effects. Effective and sustained action of a proinflammatory cytokine depends on synergy with other inflammatory cytokines and antagonism of opposing cytokines that are often highly expressed at inflammatory sites. We analyzed the effects of the inflammatory and stress agents, IL-1, TNF-α, LPS, sorbitol, and H2O2, on signaling by IL-6 and IL-10, pleiotropic cytokines that activate the Jak-Stat signaling pathway and have both pro- and anti-inflammatory actions. IL-1, TNF-α, and LPS blocked the activation of Stat DNA binding and tyrosine phosphorylation by IL-6 and IL-10, but not by IFN-γ, in primary macrophages. Inhibition of Stat activation correlated with inhibition of expression of IL-6-inducible genes. The inhibition was rapid and independent of de novo gene induction and occurred when the expression of suppressor of cytokine synthesis-3 was blocked. Inhibition of IL-6 signaling was mediated by the p38 subfamily of stress-activated protein kinases. Jak1 was inhibited at the level of tyrosine phosphorylation, indicating that inhibition occurred at least in part upstream of Stats in the Jak-Stat pathway. Experiments using Stat3 mutated at serine 727 and using truncated IL-6Rs suggested that the target of inhibition is contained within the membrane-proximal region of the cytoplasmic domain of the gp130 subunit of the IL-6 receptor and is different from the SH2 domain-containing protein-tyrosine phosphatase/suppressor of cytokine synthesis-3 docking site. These results identify a new level at which IL-1 and TNF-α modulate signaling by pleiotropic cytokines such as IL-6 and IL-10 and provide a molecular basis for the previously described antagonism of certain IL-6 actions by IL-1.

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Narrowband (312-nm) UV-B Suppresses Interferon γ and Interleukin (IL) 12 and Increases IL-4 Transcripts

Walters

Ozawa²,

Cardinale³

et al. 2003

Arch Dermatol

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Interleukin-11 therapy selectively downregulates type I cytokine proinflammatory pathways in psoriasis lesions

Cited by 204 publications

References 46 publications

An Anti-IL-12p40 Antibody Down-Regulates Type 1 Cytokines, Chemokines, and IL-12/IL-23 in Psoriasis

An Anti-IL-12p40 Antibody Down-Regulates Type 1 Cytokines, Chemokines, and IL-12/IL-23 in Psoriasis

Inhibition of IL-6 and IL-10 Signaling and Stat Activation by Inflammatory and Stress Pathways

Narrowband (312-nm) UV-B Suppresses Interferon γ and Interleukin (IL) 12 and Increases IL-4 Transcripts

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