Interleukin-31 promotes fibrosis and T helper 2 polarization in systemic sclerosis

AbstractSystemic sclerosis (SSc) is a chronic multisystem disorder characterized by fibrosis and autoimmunity. Interleukin (IL)-31 has been implicated in fibrosis and T helper (Th) 2 immune responses, both of which are characteristics of SSc. The exact role of IL-31 in SSc pathogenesis is unclear. Here we show the overexpression of IL-31 and IL-31 receptor A (IL-31RA) in dermal fibroblasts (DFs) from SSc patients. We elucidate the dual role of IL-31 in SSc, where IL-31 directly promotes collagen production in DFs and indirectly enhances Th2 immune responses by increasing pro-Th2 cytokine expression in DFs. Furthermore, blockade of IL-31 with anti-IL-31RA antibody significantly ameliorates fibrosis and Th2 polarization in a mouse model of SSc. Therefore, in addition to defining IL-31 as a mediator of fibrosis and Th2 immune responses in SSc, our study provides a rationale for targeting the IL-31/IL-31RA axis in the treatment of SSc.

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Role of CD28/B7 co-stimulation in airway T helper 2 (TH2) immune responses in asthma

Clinical & Experimental Allergy ◽

10.1046/j.1365-2222.1998.00424.x ◽

1998 ◽

Vol 28 (11) ◽

pp. 1317-1320 ◽

Cited By ~ 3

Author(s):

Lordan ◽

Jaffar

Keyword(s):

Immune Responses ◽

T Helper ◽

T Helper 2

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Significance of Interleukin (IL)-4 and IL-13 in Inflammatory Arthritis

Cells ◽

10.3390/cells10113000 ◽

2021 ◽

Vol 10 (11) ◽

pp. 3000

Author(s):

Milena Iwaszko ◽

Sylwia Biały ◽

Katarzyna Bogunia-Kubik

Keyword(s):

Inflammatory Arthritis ◽

Current Knowledge ◽

Allergic Inflammation ◽

Airway Epithelial Cells ◽

Airway Epithelial ◽

T Helper ◽

T Helper 2 ◽

Th2 Cytokine ◽

Inflammatory Processes

Interleukin (IL)-4 and IL-13 belong to the T helper 2 (Th2) cytokine family, along with IL-3, IL-5, and IL-9. These cytokines are key mediators of allergic inflammation. They have important immunomodulatory activities and exert influence on a wide variety of immune cells, such as B cells, eosinophils, basophils, monocytes, fibroblasts, endothelial cells, airway epithelial cells, smooth muscle cells, and keratinocytes. Recent studies have implicated IL-4 and IL-13 in the development of various autoimmune diseases. Additionally, these cytokines have emerged as potential players in pathogenesis of inflammatory arthritis. Recent findings suggest that the IL-4 and IL-13 might play a significant role in the downregulation of inflammatory processes underlying RA pathology, and beneficially modulate the course of the disease. This review summarizes the biological features of the IL-4 and IL-13 and provides current knowledge regarding the role of these cytokines in inflammatory arthritis.

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Predominant T Helper 2 Immune Responses againstBartonella henselaein Naturally Infected Cats

Microbiology and Immunology ◽

10.1111/j.1348-0421.2006.tb03783.x ◽

2006 ◽

Vol 50 (3) ◽

pp. 171-178 ◽

Cited By ~ 8

Author(s):

Hidenori Kabeya ◽

Makiko Sase ◽

Masaya Yamashita ◽

Soichi Maruyama

Keyword(s):

Immune Responses ◽

T Helper ◽

T Helper 2

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Crucial Role of the Interleukin 1 Receptor Family Member T1/St2 in T Helper Cell Type 2–Mediated Lung Mucosal Immune Responses

Journal of Experimental Medicine ◽

10.1084/jem.190.7.895 ◽

1999 ◽

Vol 190 (7) ◽

pp. 895-902 ◽

Cited By ~ 280

Author(s):

Anthony J. Coyle ◽

Clare Lloyd ◽

Jane Tian ◽

Trang Nguyen ◽

Christina Erikkson ◽

...

Keyword(s):

Immune Responses ◽

T Helper Cell ◽

Helper Cell ◽

Eosinophil Infiltration ◽

Cell Type ◽

T Helper ◽

Helper Cell Type ◽

Mucosal Immune Responses

T1/ST2 is an orphan receptor of unknown function that is expressed on the surface of murine T helper cell type 2 (Th2), but not Th1 effector cells. In vitro blockade of T1/ST2 signaling with an immunoglobulin (Ig) fusion protein suppresses both differentiation to and activation of Th2, but not Th1 effector populations. In a nascent Th2-dominated response, anti-T1/ST2 monoclonal antibody (mAb) inhibited eosinophil infiltration, interleukin 5 secretion, and IgE production. To determine if these effects were mediated by a direct effect on Th2 cells, we next used a murine adoptive transfer model of Th1- and Th2-mediated lung mucosal immune responses. Administration of either T1/ST2 mAb or T1/ST2-Ig abrogated Th2 cytokine production in vivo and the induction of an eosinophilic inflammatory response, but failed to modify Th1-mediated inflammation. Taken together, our data demonstrate an important role of T1/ST2 in Th2-mediated inflammatory responses and suggest that T1/ST2 may prove to be a novel target for the selective suppression of Th2 immune responses.

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Role of beta1 and beta2 subunits of the interleukin-12 receptor in determining T helper 1/T helper 2 responses in vivo in the rat

Immunology ◽

10.1046/j.1365-2567.2000.00927.x ◽

2000 ◽

Vol 99 (1) ◽

pp. 109-112 ◽

Cited By ~ 7

Author(s):

K. M. Gillespie ◽

C.-C. Szeto ◽

V. M. Betin ◽

P. W. Mathieson

Keyword(s):

Interleukin 12 ◽

T Helper ◽

T Helper 1 ◽

T Helper 2

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Role of IL-4, IL-13, and STAT6 in inflammation-induced hypercontractility of murine smooth muscle cells

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.2002.282.2.g226 ◽

2002 ◽

Vol 282 (2) ◽

pp. G226-G232 ◽

Cited By ~ 100

Author(s):

Hirotada Akiho ◽

Patricia Blennerhassett ◽

Yikang Deng ◽

Stephen M. Collins

Keyword(s):

Smooth Muscle ◽

Smooth Muscle Cells ◽

Trichinella Spiralis ◽

Muscle Cells ◽

Dependent Manner ◽

T Helper ◽

Concentration Dependent Manner ◽

T Helper 2 ◽

Muscularis Externa

T helper 2 (Th2) cytokines interleukin (IL)-4 and IL-13, which activate signal transducer and activator of transcription 6 (STAT6) are expressed in the muscularis externa during nematode infection and are candidate mediators of the associated hypercontractility. To determine the locus of action of these cytokines, we examined the IL-4- and IL-13-induced hypercontractility of the isolated muscle cells from STAT6 +/+ and STAT6 −/− mice. We compared the results with cells isolated from Trichinella spiralis-infected STAT6 +/+ and STAT6 −/− mice. Carbamylcholine chloride (Carbachol) induced the contraction of jejunal muscle cells in a concentration-dependent manner maximal contraction (Rmax26.7 ± 1.9%). Cells from T. spiralis-infected STAT6 −/− mice showed the hypertrophy (cell lengths 41.4 ± 0.8 to 89.0 ± 8.7 μm) and hypercontractility (Rmax37.5 ± 1.3%) induced by infection. IL-4Rα mRNA was detected in dispersed smooth muscle cells. Incubation of longitudinal muscle-myenteric plexus (LMMP) with IL-4 and IL-13 enhanced Carbachol-induced muscle contraction (Rmax35.5 ± 1.9 and 32.4 ± 2.9%, respectively). Incubation of LMMP from STAT6 −/− mice with IL-4 did not enhance the contraction. The hypercontractility in T. spiralis-infected mice was attenuated in STAT6 −/− mice ( P < 0.02). These results indicate both IL-4 and IL-13 induce hypercontractility of muscle cells via the STAT6 pathway, and this is the basis for hypercontractility observed in T. spiralis-infected mice.

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Reduced development of COVID-19 in children reveals molecular checkpoints gating pathogenesis illuminating potential therapeutics

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2012358117 ◽

2020 ◽

Vol 117 (40) ◽

pp. 24620-24626 ◽

Cited By ~ 9

Author(s):

Jonathan Baruch Steinman ◽

Fok Moon Lum ◽

Peggy Pui-Kay Ho ◽

Naftali Kaminski ◽

Lawrence Steinman

Keyword(s):

Severe Acute Respiratory Syndrome ◽

Immune Responses ◽

Respiratory Tract ◽

Global Economy ◽

T Cell Immunity ◽

T Helper ◽

T Helper 2 ◽

Cell Immunity ◽

The Impact ◽

Potential Therapeutics

The reduced development of COVID-19 for children compared to adults provides some tantalizing clues on the pathogenesis and transmissibility of this pandemic virus. First, ACE2, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptor, is reduced in the respiratory tract in children. Second, coronavirus associated with common colds in children may offer some protection, due to cross-reactive humoral immunity and T cell immunity between common coronaviruses and SARS-CoV-2. Third, T helper 2 immune responses are protective in children. Fourth, surprisingly, eosinophilia, associated with T helper 2, may be protective. Fifth, children generally produce lower levels of inflammatory cytokines. Finally, the influence of the downturn in the global economy, the impact of living in quarters among families who are the most at risk, and factors including the openings of some schools, are considered. Those most disadvantaged socioeconomically may suffer disproportionately with COVID-19.

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