Identification of tgh-2, a Filarial Nematode Homolog of Caenorhabditis elegans daf-7 and Human Transforming Growth Factor β, Expressed in Microfilarial and Adult Stages of Brugia malayi

ABSTRACT A novel member of the transforming growth factor β (TGF-β) family has been identified in the filarial nematode parasiteBrugia malayi by searching the recently developed Expressed Sequence Tag (EST) database produced by the Filarial Genome Project. Designated tgh-2, this new gene shows most similarity to a key product regulating dauer larva formation in Caenorhabditis elegans (DAF-7) and to the human down-modulatory cytokine TGF-β. Homology to DAF-7 extends throughout the length of the 349-amino-acid (aa) protein, which is divided into an N-terminal 237 aa, including a putative signal sequence, a 4-aa basic cleavage site, and a 108-aa C-terminal active domain. Similarity to human TGF-β is restricted to the C-terminal domain, over which there is a 32% identity between TGH-2 and TGF-β1, including every cysteine residue. Expression of tgh-2 mRNA has been measured over the filarial life cycle. It is maximal in the microfilarial stage, with lower levels of activity around the time of molting within the mammal, but continues to be expressed by mature adult male and female parasites. Expression in both the microfilaria, which is in a state of arrested development, and the adult, which is terminally differentiated, indicates that tgh-2 may play a role other than purely developmental. This is consistent with our observation that TGH-2 is secreted by adult worms in vitro. Recombinant TGH-2 expressed in baculovirus shows a low level of binding to TGF-β-receptor bearing mink lung epithelial cells (MELCs), which is partially inhibited (16 to 39%) with human TGF-β, and activates plasminogen activator inhibitor-1 transcription in MELCs, a marker for TGF-β-mediated transduction. Further tests will be required to establish whether the major role of B. malayi TGH-2 (Bm-TGH-2) is to modulate the host immune response via the TGF-β pathway.

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SMA-10 Is a Non-Canonical Member of the TGF-β Sma/Mab Pathway and Immunity Regulator via the DAF-2 Insulin Receptor in Caenorhabditis elegans

International Journal of Molecular Sciences ◽

10.3390/ijms22020638 ◽

2021 ◽

Vol 22 (2) ◽

pp. 638

Author(s):

María Pilar de Lucas ◽

Marta Jiménez ◽

Paloma Sánchez-Pavón ◽

Alberto G. Sáez ◽

Encarnación Lozano

Keyword(s):

Immune Response ◽

Body Size ◽

Caenorhabditis Elegans ◽

Growth Factor ◽

Insulin Receptor ◽

Transforming Growth Factor ◽

Transforming Growth Factor Β ◽

Small Male ◽

Positive Modulator ◽

Growth Factor Signalling

Transforming growth factor β (TGF-β) signalling pathways are highly conserved across metazoa and play essential roles not only during development but also in adult tissue maintenance. Alterations of these pathways usually result in a plethora of pathologies. In the nematode Caenorhabditis elegans, the TGF-β Sma/Mab (small/male abnormal) pathway regulates various worm phenotypes such as body size, immune response, ageing, matricide and reproductive span. SMA-10 has been described as a positive modulator of worm body size through the TGF-β Sma/Mab pathway. To better understand if SMA-10 is a core component of the pathway, we use gene epistatic analysis to assess the contribution of SMA-10 to various phenotypes regulated by TGF-β Sma/Mab. We confirm that SMA-10 controls body size and find that it also affects the matricide and reproductive span of the nematodes. However, neither male tail formation (previously reported) nor ageing appeared altered. Lastly, although null sma-10 worms are more susceptible to Pseudomonas aeruginosa infections than wild-types, this response does not depend on TGF-β Sma/Mab but on the insulin receptor DAF-2. We also show that the expression of sma-10 in either hypodermis or intestine fully rescues the wild-type immune response. Our results contribute to understanding the role of SMA-10 as a context-dependent component of TGF-β Sma/Mab, and reveal a function of SMA-10 in immunity in association to the Insulin/insulin-like growth factor signalling (IIS) pathway.

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A Component-Resolved Therapeutic Vaccine for Cockroach Allergy Made of Per a 9 and Transforming Growth Factor-β Homologue, an Immunosuppressive Protein of Brugia malayi

Frontiers in Immunology ◽

10.3389/fimmu.2021.676558 ◽

2021 ◽

Vol 12 ◽

Author(s):

Pannathee Prangtaworn ◽

Kodchakorn Mahasongkram ◽

Atiporn Saeung ◽

Urai Chaisri ◽

Watee Seesuay ◽

...

Keyword(s):

Growth Factor ◽

Transforming Growth Factor Beta ◽

Periplaneta Americana ◽

Transforming Growth Factor ◽

Therapeutic Vaccine ◽

Brugia Malayi ◽

Transforming Growth Factor Β ◽

Therapeutic Effects ◽

Allergen Specific Immunotherapy

Allergen-specific-immunotherapy (ASIT) can cause long-term resolution of allergic diseases, reduces drug use and chances of new allergen sensitization. Nevertheless, therapeutic vaccine and data on ASIT efficacy for cockroach (CR) allergy are relatively scarce. In this study, efficacy and mechanism of a novel intranasal vaccine consisting of liposome (L)-entrapped mixture of American CR (Periplaneta americana) major allergen (Per a 9) and immunosuppressive protein of Brugia malayi nematode named transforming growth factor-beta homologue (TGH) in treatment of CR allergy were investigated along with two other vaccines (L-Per a 9 alone and L-TGH alone). All three vaccines could reduce pathogenic type 2 response and lung immunopathology in the vaccines-treated CR-allergic mice, but by different mechanisms. L-Per a 9 caused a deviation of the pathogenic type 2 to type 1 response (IFN-γ-upregulation), whereas the L-(TGH + Per a 9) and L-TGH generated regulatory immune responses including up-expression of immunosuppressive cytokine genes and increment of serum adenosine and lung indoleamine-2,3-dioxygenase-1 which are signatures of regulatory T cells (Tregs) and tolerogenic dendritic cells, respectively. The L-(TGH + Per a 9) should be further evaluated towards clinical application, as this vaccine has a propensity to induce broadly effective therapeutic effects for inhalant allergies.

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Interleukin-1α, Epidermal Growth Factor, and Transforming Growth Factor-β Exhibit Differential Kinetics on Endothelin-1 Synthesis in Amnion Cells

Journal of the Society for Gynecologic Investigation ◽

10.1016/s1071-5576(97)00102-0 ◽

1998 ◽

Vol 5 (1) ◽

pp. 25-30 ◽

Cited By ~ 2

Author(s):

D McKenna

Keyword(s):

Growth Factor ◽

Epidermal Growth Factor ◽

Transforming Growth Factor ◽

Transforming Growth Factor Β ◽

Endothelin 1 ◽

Epidermal Growth ◽

Interleukin 1Α

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Perianale Fisteln bei CED: vom Mausmodell zur Klinik

Therapeutische Umschau ◽

10.1024/0040-5930/a001000 ◽

2018 ◽

Vol 75 (5) ◽

pp. 287-294

Author(s):

Michael Scharl

Keyword(s):

Growth Factor ◽

Morbus Crohn ◽

Transforming Growth Factor ◽

Transforming Growth Factor Β ◽

Interleukin 13

Zusammenfassung. Fisteln stellen nach wie vor eine der wichtigsten Komplikationen bei Patienten mit Morbus Crohn dar. Bei mindestens einem Drittel aller Morbus Crohn Patienten treten im Laufe der Erkrankung Fisteln auf. Eine dauerhafte Heilung der Fistel wird jedoch, auch unter Ausschöpfung sämtlicher medikamentöser und chirurgischer Therapieoptionen, nur in rund einem Drittel dieser Patienten erreicht. Der genaue molekulare Mechanismus der Fistelentstehung ist bis heute nicht ganz klar. Aus histopathologischer Sichtweise stellen Fisteln eine röhrenartige Struktur dar, welche von flachen epithelartigen Zellen ausgekleidet ist. Als ursächlicher Entstehungsmechanismus wird dabei die sogenannte epitheliale-zu-mesenchymale Transition (EMT) angesehen und es kann eine starke Expression der Entzündungsmediatoren Tumor Nekrose Faktor, Interleukin-13 und Transforming Growth Factor β in den Fistelarealen nachgewiesen werden. Zusätzlich zu den bereits etablierten, medikamentösen Therapieoptionen, also Antibiotika, Immunmodulatoren und anti-TNF Antikörper, stellt insbesondere der Einsatz der mesenchymalen Stammzelltherapie einen erfolgversprechenden Therapieansatz für die Zukunft dar.

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