Identification of a Novel Cytokine, ML-1, and Its Expression in Subjects with Asthma

Kawaguchi, Mio; Onuchic, Luiz Fernando; Li, Xiaodong; Essayan, David M.; Schroeder, John T.; Xiao, Huamei; Liu, Mark C.; Krishnaswamy, Guha; Germino, Gregory G.; Huang, Shau‐Ku

doi:10.4049/jimmunol.167.8.4430

Cited by 169 publications

(216 citation statements)

References 24 publications

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“…Similarly, immunoprecipitation of culture supernatants with anti-IL-17F antibody also pulled down IL-17, which confirmed the existence of a heterocomplex. Under reducing conditions, these proteins migrated between 17 and 21 kDa as monomers, consistent with previously reported molecular www.cell-research.com | Cell Research Seon Hee Chang and Chen Dong 437 npg weight of IL-17 [9] or IL-17F [19]. Thus in addition to homodimers, IL-17 and IL-17F also form a heterodimer when overexpressed in 293T cells.…”

Section: Il-17 and Il-17f Form A Heterodimersupporting

confidence: 74%

“…A recent study demonstrated coordinated regulation of IL-17 and IL-17F gene transcription during THi differentiation, possibly through chromatin remodeling at this locus [18]. Expression of IL-17F has also been linked with human inflammatory diseases, including asthma [19]. Treatment of human airway epithelial cells, vein endothelial cells, and fibroblasts with IL-17F induced the expression of IL-6, IL-8, GROα, ENA-78, transforming growth factor-β (TGF-β), MCP-1 (Monocyte chemotactic protein-1, CCL2), G-CSF, granulocyte-macrophage colony-stimulating factor (GM-CSF) and intercellular adhesion molecule-1 (ICAM-1) [19][20][21][22][23].…”

Section: Introductionmentioning

confidence: 99%

“…Expression of IL-17F has also been linked with human inflammatory diseases, including asthma [19]. Treatment of human airway epithelial cells, vein endothelial cells, and fibroblasts with IL-17F induced the expression of IL-6, IL-8, GROα, ENA-78, transforming growth factor-β (TGF-β), MCP-1 (Monocyte chemotactic protein-1, CCL2), G-CSF, granulocyte-macrophage colony-stimulating factor (GM-CSF) and intercellular adhesion molecule-1 (ICAM-1) [19][20][21][22][23]. Although the receptor of IL-17F is yet to be identified, it at least in part may utilize IL-17RA [24].…”

Section: Introductionmentioning

confidence: 99%

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A novel heterodimeric cytokine consisting of IL-17 and IL-17F regulates inflammatory responses

2007

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Section: Il-17 and Il-17f Form A Heterodimersupporting

confidence: 74%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A novel heterodimeric cytokine consisting of IL-17 and IL-17F regulates inflammatory responses

2007

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“…Although several studies have examined the effects of mouse IL-17A/A, most comparisons of IL-17A/A and IL-17F/F activity have been reported using human cytokines. In these studies, human IL-17A/A was either more potent or equally as potent as IL-17F/F in inducing certain proinflammatory mediators from epithelial cells in vitro (10,11,23). Because IL-17A/A and IL-17F/F are glycosylated proteins, a recombinant protein may have different activity depending on whether a prokaryotic or eukaryotic cell produced it.…”

Section: Discussionmentioning

confidence: 99%

An IL-17F/A Heterodimer Protein Is Produced by Mouse Th17 Cells and Induces Airway Neutrophil Recruitment

Liang

Long²,

Bennett³

et al. 2007

The Journal of Immunology

316

252

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IL-17A and IL-17F are related homodimeric proteins of the IL-17 family produced by Th17 cells. In this study, we show that mouse Th17 cells also produce an IL-17F/A heterodimeric protein. Whereas naive CD4+ T cells differentiating toward the Th17 cell lineage expressed IL-17F/A in higher amounts than IL-17A/A homodimer and in lower amounts than IL-17F/F homodimer, differentiated Th17 cells expressed IL-17F/A in higher amounts than either homodimer. In vitro, IL-17F/A was more potent than IL-17F/F and less potent than IL-17A/A in regulating CXCL1 expression. Neutralization of IL-17F/A with an IL-17A-specific Ab, and not with an IL-17F-specific Ab, reduced the majority of IL-17F/A-induced CXCL1 expression. To study these cytokines in vivo, we established a Th17 cell adoptive transfer model characterized by increased neutrophilia in the airways. An IL-17A-specific Ab completely prevented Th17 cell-induced neutrophilia and CXCL5 expression, whereas Abs specific for IL-17F or IL-22, a cytokine also produced by Th17 cells, had no effects. Direct administration of mouse IL-17A/A or IL-17F/A, and not IL-17F/F or IL-22, into the airways significantly increased neutrophil and chemokine expression. Taken together, our data elucidate the regulation of IL-17F/A heterodimer expression by Th17 cells and demonstrate an in vivo function for this cytokine in airway neutrophilia.

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“…It has been shown by reverse transcriptase-PCR experiments that the cytokines are expressed in activated human CD4ϩ T cells (11,12). Expression of IL-17F and IL-17A has also been observed in tissue samples from various autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, psoriasis, inflammatory bowel disease, and asthma (2,3,(13)(14)(15)(16)(17)(18)(19)(20)(21)(22).…”

mentioning

confidence: 99%

Identification of an Interleukin 17F/17A Heterodimer in Activated Human CD4+ T Cells

Wright

Guo²,

Quazi

et al. 2007

Journal of Biological Chemistry

291

232

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IL-17F and IL-17A are members of the IL-17 pro-inflammatory cytokine family. IL-17A has been implicated in the pathogenesis of autoimmune diseases. IL-17F is a disulfidelinked dimer that contains a cysteine-knot motif. We hypothesized that IL-17F and IL-17A could form a heterodimer due to their sequence homology and overlapping pattern of expression. We evaluated the structure of recombinant IL-17F and IL-17A proteins, as well as that of natural IL-17F and IL-17A derived from activated human CD4؉ T cells, by enzyme-linked immunosorbent assay, immunoprecipitation followed by Western blotting, and mass spectrometry. We find that both IL-17F and IL-17A can form both homodimeric and heterodimeric proteins when expressed in a recombinant system, and that all forms of the recombinant proteins have in vitro functional activity. Furthermore, we find that in addition to the homodimers of IL-17F and IL-17A, activated human CD4؉ T cells also produce the IL-17F/IL-17A heterodimer. These data suggest that the IL-17F/IL-17A heterodimer may contribute to the T cell-mediated immune responses.Interleukins 17F 3 and 17A (IL-17A) are closely related members of the IL-17 cytokine family, and share 50% amino acid identity. Studies in the mouse have identified Th17 cells as a distinct CD4ϩ T cell lineage that is defined by the production of IL-17F and IL-17A (1-7). IL-6 and transforming growth factor-␤ (TGF-␤) are required for the differentiation of naïve CD4ϩ T cells to Th17 cells (1,8), which are maintained in the presence of IL-23 and IL-1␤. Conversely, IL-4 and interferon-␥ can inhibit the development of Th17 cells (9, 10). Th17 cells have been implicated in the pathology of mouse autoimmune disease models (2).Expression of IL-17F and IL-17A has been detected in activated human peripheral blood lymphocytes. It has been shown by reverse transcriptase-PCR experiments that the cytokines are expressed in activated human CD4ϩ T cells (11,12). Expression of IL-17F and IL-17A has also been observed in tissue samples from various autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, psoriasis, inflammatory bowel disease, and asthma (2, 3, 13-22).The crystal structure of IL-17F has been solved and shows that the protein forms a disulfide-linked dimeric glycoprotein (23). IL-17A is also a disulfide-linked homodimeric glycoprotein (24), although crystal structure or data defining the precise subunit interactions are lacking. The IL-17F homodimer includes a classical cysteine knot motif, which is found in the TGF-␤, bone morphogenetic protein, and nerve growth factor superfamilies (25, 26). One difference in the cysteine knot motif of IL-17F compared with the other known cysteine knot protein families is that it only utilizes four cysteines instead of the classical six cysteines to form the knot.There have been reports that some of the cysteine knot family members can exist as heterodimers in vivo. TGF-␤1.2 and -␤2.3 were identified in bovine bone extracts, whereas inhibin and activin AB have been found in gonadal fluids (27...

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Identification of a Novel Cytokine, ML-1, and Its Expression in Subjects with Asthma

Cited by 169 publications

References 24 publications

A novel heterodimeric cytokine consisting of IL-17 and IL-17F regulates inflammatory responses

A novel heterodimeric cytokine consisting of IL-17 and IL-17F regulates inflammatory responses

An IL-17F/A Heterodimer Protein Is Produced by Mouse Th17 Cells and Induces Airway Neutrophil Recruitment

Identification of an Interleukin 17F/17A Heterodimer in Activated Human CD4+ T Cells

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