TGFβ in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-Producing T cells

Interleukin-17 Family Members and Inflammation

The Biological Functions of T Helper 17 Cell Effector Cytokines in Inflammation

For over 35 years, immunologists have divided T-helper (TH) cells into functional subsets. T-helper type 1 (TH1) cells—long thought to mediate tissue damage—might be involved in the initiation of damage, but they do not sustain or play a decisive role in many commonly studied models of autoimmunity, allergy and microbial immunity. A major role for the cytokine interleukin-17 (IL-17) has now been described in various models of immune-mediated tissue injury, including organ-specific autoimmunity in the brain, heart, synovium and intestines, allergic disorders of the lung and skin, and microbial infections of the intestines and the nervous system. A pathway named TH17 is now credited for causing and sustaining tissue damage in these diverse situations. The TH1 pathway antagonizes the TH17 pathway in an intricate fashion. The evolution of our understanding of the TH17 pathway illuminates a shift in immunologists' perspectives regarding the basis of tissue damage, where for over 20 years the role of TH1 cells was considered paramount.

http://cnc.cj.uc.pt/BEB/private/pdfs/2007-2008/Immunology/A/Rev_paper_A5.pdf

A brief history of T(H)17, the first major revision in the T(H)1/T(H)2 hypothesis of T cell-mediated tissue damage.

Pulmonary defense against environmental injury depends on airway mucus, which traps inhaled toxins that are then cleared from the lungs by ciliary beating and cough. This review examines the normal and abnormal formation and clearance of mucus, as well as the therapy of mucus dysfunction.

/pdf/airway-mucus-function-and-dysfunction-332cc0o62m.pdf

Airway mucus function and dysfunction.

Stimulation of Airway Mucin Gene Expression by Interleukin (IL)-17 through IL-6 Paracrine/Autocrine Loop

Gel-forming mucins are major contributors to the viscoelastic properties of mucus secretion. Currently, four gel-forming mucin genes have been identified: MUC2, MUC5AC, MUC5B, and MUC6. All these genes have five major cysteine-rich domains (four von Willebrand factor [vWF] C or D domains and one Cystine-knot [CT] domain) as their distinctive features, in contrast to other non-gel-forming type of mucins. The CT domain is believed to be involved in the initial mucin dimer formation and have very succinct relationship between different gel-forming mucins across different species. Because of gene duplication and evolutional modification, it is very likely that other gel-forming mucin genes exist. To search for new gel-forming mucin candidate genes, a "Hidden Markov Model"(HMM) was built from the common features of the CT domains of those gel-forming mucins. By using this model to screen all protein databases as well as the six-frame translated expression sequence tag and translated human genomic databases, we identified a locus located at the peri-centromere region of human chromosome 12 and the corresponding homologous region of mouse chromosome 15. We cloned the 3' end of this gene and its mouse homolog. We found one vWF C domain, one CT domain, and various mucin-like threonine/serine-rich repeats. Phylogenetic analysis indicated the close relationship between this gene and the submaxillary mucin from porcine and bovine. A polydispersed signal was observed on the Northern blot, which indicates very large mRNA size. Further analysis of the upstream genomic sequences generated from human and mouse genome projects revealed three additional vWF D domains and many mucin-like threonine/serine-rich repeats. The expression of this gene is restricted to the mucous cells of various glandular tissues, including sublingual gland, submandibular gland, and submucosal gland of the trachea. Based on the chronological convention, we have given the name MUC19 to the human ortholog and Muc19 to the mouse.

Genome-wide search and identification of a novel gel-forming mucin MUC19/Muc19 in glandular tissues.

Human mucin (MUC) 5B gene expression in human airway epithelium was studied in both tissue sections and cultures of tracheobronchial epithelial (TBE) cells. In situ hybridization demonstrated that MUC5B message was expressed mainly in the mucous cells of submucosal glands of normal human airway tissues. Nevertheless, an elevated MUC5B message level could be seen in surface goblet cells from patients with airway diseases and inflammation. Regardless of the airway tissue sources, MUC5B message was regulated by all-trans-retinoic acid (RA) and culture conditions in both primary and passage-1 cultures of TBE cells. MUC5B message, to a lesser extent, was also found in the immortalized epithelial cell line HBE1, but not in BEAS-2B cells. To elucidate the molecular mechanism of MUC5B gene expression, a genomic clone was obtained and sequenced for the amino terminal and the 5'-flanking region of MUC5B gene. A luciferase reporter construct containing 4,169 base pairs of the 5'-flanking region of MUC5B gene demonstrated a cell type-specific basal promoter activity in transfection studies. Both RA and the air-liquid interface culture condition further enhanced this promoter activity. These results suggest that the 5'-flanking region of MUC5B gene contains cis-elements that are potentially involved in the regulation of MUC5B gene expression.

https://www.atsjournals.org/doi/pdf/10.1165/ajrcmb.25.5.4298

Characterization of human mucin 5B gene expression in airway epithelium and the genomic clone of the amino-terminal and 5'-flanking region.

The effects of extracellular nucleotide triphosphates on the stimulation of mucin production by airway epithelial cells were examined. The order of potency in stimulating mucin secretion in primary cultures of human tracheobronchial epithelial cells is: uridine 5'-triphosphate (UTP) approximately equal to adenosine 5'-triphosphate (ATP) approximately equal to ATP-gamma-S > uridine 5'-diphosphate approximately equal to adenosine 5'-diphosphate > alpha,beta-methylene ATP >> adenosine. However, only UTP can increase mucin gene (MUC5AC, MUC5B) expression; ATP and other analogues have no stimulatory effect. The stimulation of MUC5AC and MUC5B expression by UTP is time- and dose-dependent. A similar effect on the elevation of mucous cell population in mouse airway epithelium can be demonstrated in vivo by an intratracheal instillation of UTP-saline solution. The stimulatory effect of UTP or ATP on mucin secretion was inhibited by pertussis toxin, U73122, and Calphostin C, but not by PD98059, suggesting a G-protein/ phospholipase (PL) C/protein kinase (PK) C-dependent and mitogen-activated protein kinase (MAPK)-independent signaling pathway. However, the stimulatory effect of UTP on mucin gene expression was sensitive to pertussis toxin and PD98059, but not to Calphostin C and U73122, suggesting a G-protein/MAPK-dependent and PLC/PKC-independent signaling pathway. These findings are the first demonstration that UTP, a pyrimidine nucleotide triphosphate, can enhance both mucin secretion and mucin gene expression through different signaling pathways.

https://www.atsjournals.org/doi/pdf/10.1165/ajrcmb.25.4.4413

Differential regulation of airway mucin gene expression and mucin secretion by extracellular nucleotide triphosphates.

Using a BLAST-searching approach, we identified a mouse expressed sequence tag (EST) clone (AA038672) showing great similarity to the 3 ′ end of the human MUC5B gene. The clone was named “3pmmuc5b-1” after complete nucleotide sequencing (Genbank Accession, AF369933). A subsequent search of the mouse genome database with the 3pmmuc5b-1 sequence identified two overlapping genomic clones (AC020817 and AC020794) that contained the sequence of both 3pmmuc5b-1 and the mouse Muc5ac gene. Like their human homologs, the genomic order of the mouse Muc genes is 5 ′ -Muc5ac-Muc5b-3 ′ . These results suggest that the newly identified EST clone, 3pmmuc5b-1, is part of the 3 ′ portion of the mouse Muc5b gene. In situ hybridization demonstrated that this putative mouse Muc5b message was expressed in a restricted manner in the sublingual gland region of the tongue and the submucosal gland region of the mouse trachea in a normal animal. However, the gene expression was greatly enhanced in airway surface epithelium and the ...

https://www.atsjournals.org/doi/pdf/10.1164/ajrccm.164.6.2012114

Yu Hua Zhao

Papers

Stimulation of Airway Mucin Gene Expression by Interleukin (IL)-17 through IL-6 Paracrine/Autocrine Loop

Genome-wide search and identification of a novel gel-forming mucin MUC19/Muc19 in glandular tissues.

Characterization of human mucin 5B gene expression in airway epithelium and the genomic clone of the amino-terminal and 5'-flanking region.

Differential regulation of airway mucin gene expression and mucin secretion by extracellular nucleotide triphosphates.

In silico cloning of mouse Muc5b gene and upregulation of its expression in mouse asthma model