IL-4 enhances IFN-λ1 (IL-29) production by plasmacytoid DCs via monocyte secretion of IL-1Ra

Blood ◽  
2010 ◽  
Vol 115 (21) ◽  
pp. 4185-4190 ◽  
Author(s):  
Nicholas J. Megjugorac ◽  
Grant E. Gallagher ◽  
Grant Gallagher
Keyword(s):  
Inhibitory Effect ◽  
T Helper ◽  
Th2 Response ◽  
T Helper 2 ◽  
Peripheral Lymphocytes ◽  
Intermediary Cell ◽  
Human Peripheral Lymphocytes ◽  
Plasmacytoid Dcs ◽  
Type Iii Interferon ◽  
Stimulation Of

The type-III interferon (IFN) family is composed of 3 molecules in humans: IFN-λ1 (interleukin-29 [IL-29]), IFN-λ2 (IL-28A), and IFN-λ3 (IL-28B), each of which signals through the same receptor complex. Plasmacytoid dendritic cells (pDCs) are major IFN-λ producers among peripheral lymphocytes. Recently, it has been shown that IFN-λ1 exerts a powerful inhibitory effect over the T-helper 2 (Th2) response by antagonizing the effect of IL-4 on CD4+ T cells and inhibiting the production of Th2-associated cytokines. Here, we asked whether Th2 cytokines exert reciprocal control over IFN-λ production. IL-4 treatment during stimulation of human peripheral lymphocytes significantly elevated IFN-λ1 transcription and secretion. However, pDCs were not directly responsive to IL-4. Using depletion and reconstitution experiments, we showed that IL-4–responsive monocytes are an intermediary cell, responding to IL-4 by elevating their secretion of IL-1 receptor antagonist (IL-Ra); this IL-1Ra acts on pDCs to elevate their IFN-λ1 output. Thus, our experiments revealed a novel mechanism for regulation of both IFN-λ1 production and pDC function, and suggests an expanded immunomodulatory role for Th2-associated cytokines.

Remission of Alopecia Universalis after 1 Year of Treatment with Dupilumab in a Patient with Severe Atopic Dermatitis

2021 ◽  
pp. 1-4
Author(s):  
Maurizio Romagnuolo ◽  
Mauro Barbareschi ◽  
Simona Tavecchio ◽  
Luisa Angileri ◽  
Silvia Mariel Ferrucci
Keyword(s):  
Atopic Dermatitis ◽  
Skin Disorder ◽  
Human Monoclonal Antibody ◽  
Severe Atopic Dermatitis ◽  
T Helper ◽  
T Helper 1 ◽  
Th2 Response ◽  
Alopecia Universalis ◽  
T Helper 2 ◽  
Relapsing Remitting

Alopecia areata (AA), an autoimmune disease with a relapsing-remitting course, represents the second cause of non­scarring alopecia worldwide and is associated with several comorbidities, notably atopic dermatitis (AD). In particular, AD is related to its more severe forms alopecia totalis (AT) and alopecia universalis (AU) [Nat Rev Dis Primers. 2017;3:17011]. Considering that AA has been classified as T helper 1-driven disease, whereas AD is the prototypical T helper 2 (Th2)-driven skin disorder, recent studies suggest that these forms may underlie a different chemokine expression resulting in a Th2 skewing as a key pathomechanism that could explain this association [JAMA Dermatol. 2015 May;151(5):522–8]. Several reports showed that dupilumab, a fully human monoclonal antibody targeting the interleukin 4α receptor and thus downregulating Th2 response, led to an improvement of AA associated with AD; most of these patients were females with AT or AU, early-onset AD, and atopic comorbidities [Exp Dermatol. 2020 Aug;29(8):726–32]. We report here a case to further support this hypothesis.

scholarly journals Prostaglandin-E2 is a potent inhibitor of human interleukin 12 production.

1995 ◽  
Vol 181 (2) ◽  
pp. 775-779 ◽  
Author(s):  
T C van der Pouw Kraan ◽  
L C Boeije ◽  
R J Smeenk ◽  
J Wijdenes ◽  
L A Aarden
Keyword(s):  
Human Immunodeficiency Virus ◽  
Prostaglandin E2 ◽  
Potent Inhibitor ◽  
Allergic Diseases ◽  
Inhibitory Effect ◽  
Blood Cultures ◽  
Interleukin 12 ◽  
T Helper ◽  
Th2 Response ◽  
Immunodeficiency Virus

During human immunodeficiency virus infection and allergic diseases, characterized by a dominant T helper (Th) 2 response, overproduction of prostaglandin E2 (PGE2) is observed. In this paper we studied the effect of PGE2 on interleukin (IL)-12 synthesis, because this cytokine has been described to be essential in induction of Th1 responses. IL-12 synthesis was induced in monocytes that were stimulated with Neisseria meningitidis-derived lipopolysaccharide in whole blood cultures. PGE2 almost completely inhibited lipopolysaccharide induced IL-12 production, whereas IL-6 production was only partially inhibited by PGE2. In contrast, the production of IL-10 was approximately twofold enhanced at these conditions. The effects of PGE2 were due to its cAMP-inducing capacity, since they could be mimicked by other cAMP inducers. Recombinant human IL-10 also inhibited IL-12 and IL-6 production. However, the inhibitory effect of PGE2 on IL-12 production was independent of IL-10 since neutralizing anti-IL-10 antibodies were unable to reverse this inhibition. These results suggest that the capacity of an antigen to induce PGE2 synthesis may play a crucial role in the development of either a Th1 or Th2 response.

Selective disruption of interleukin 4 autocrine-regulated loop by a tyrosine kinase inhibitor restricts activity of T-helper 2 cells

Blood ◽  
2000 ◽  
Vol 95 (12) ◽  
pp. 3816-3822 ◽  
Author(s):  
Li Hua Wang ◽  
Robert A. Kirken ◽  
Xiao Yi Yang ◽  
Rebecca A. Erwin ◽  
Luis DaSilva ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Cell Line ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Inhibitory Effect ◽  
Interleukin 4 ◽  
Th2 Cells ◽  
T Helper ◽  
Th1 Cell ◽  
T Helper 2

Interleukin (IL) 4 is a potent immunomodulatory cytokine secreted by T-helper 2 (Th2) cells and Th2 mast cells that promotes the commitment of cells. However, unregulated production and release of IL-4 can exacerbate allergic reactions and increase susceptibility to infectious organisms and viruses. Here, we present evidence that AG-490, a Janus tyrosine kinase (JAK) 2-JAK3 inhibitor, effectively blocked IL-4 gene expression and secretion in the Th2 cell line D10 that was not occurring after anti-CD3 antibody stimulation, whereas AG-490 had no inhibitory effect on production of other Th2 cytokines or cytokines synthesized by the corresponding Th1 cell line clone 29. AG-490 potently inhibited IL-4–mediated proliferation of both D10 and the IL-4–dependent cell line CT.4S. Moreover, AG-490 markedly inhibited IL-4 activation of JAK3 and blocked the downstream activation of signal transducer and activator of transcription 6, as judged by tyrosine phosphorylation, DNA binding, and transcription assays. In contrast, AG-490 did not affect tumor necrosis factor  activation of NF-κB at similar concentrations of drug. These data suggest that tyrosine kinase inhibitors that inhibit JAK3 may have previously unrecognized and selective clinical potential as immunotherapeutic drugs to treat Th2-mediated diseases driven by IL-4.

scholarly journals Flexibility of Mouse Classical and Plasmacytoid-derived Dendritic Cells in Directing T Helper Type 1 and 2 Cell Development

2003 ◽  
Vol 197 (1) ◽  
pp. 101-109 ◽  
Author(s):  
André Boonstra ◽  
Carine Asselin-Paturel ◽  
Michel Gilliet ◽  
Chad Crain ◽  
Giorgio Trinchieri ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Ex Vivo ◽  
Cell Development ◽  
T Helper ◽  
Th2 Response ◽  
Th1 Cell ◽  
Antigen Dose ◽  
Effector Cells ◽  
Stimulation Of

Distinct dendritic cell (DC) subsets have been suggested to be preprogrammed to direct either T helper cell (Th) type 1 or Th2 development, although more recently different pathogen products or stimuli have been shown to render these DCs more flexible. It is still unclear how distinct mouse DC subsets cultured from bone marrow precursors, blood, or their lymphoid tissue counterparts direct Th differentiation. We show that mouse myeloid and plasmacytoid precursor DCs (pDCs) cultured from bone marrow precursors and ex vivo splenic DC subsets can induce the development of both Th1 and Th2 effector cells depending on the dose of antigen. In general, high antigen doses induced Th1 cell development whereas low antigen doses induced Th2 cell development. Both cultured and ex vivo splenic plasmacytoid-derived DCs enhanced CD4+ T cell proliferation and induced strong Th1 cell development when activated with the Toll-like receptor (TLR)9 ligand CpG, and not with the TLR4 ligand lipopolysaccharide (LPS). The responsiveness of plasmacytoid pDCs to CpG correlated with high TLR9 expression similarly to human plasmacytoid pDCs. Conversely, myeloid DCs generated with granulocyte/macrophage colony-stimulating factor enhanced Th1 cell development when stimulated with LPS as a result of their high level of TLR4 expression. Polarized Th1 responses resulting from high antigen dose were not additionally enhanced by stimulation of DCs by TLR ligands. Thus, the net effect of antigen dose, the state of maturation of the DCs together with the stimulation of DCs by pathogen-derived products, will determine whether a Th1 or Th2 response develops.

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