Cutting Edge: Hemokinin Has Substance P-Like Function and Expression in Inflammation

Metwali, Ahmed; Blum, Arthur M.; Elliott, David E.; Setiawan, Tommy; Weinstock, Joel V.

doi:10.4049/jimmunol.172.11.6528

Cited by 61 publications

(42 citation statements)

References 30 publications

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“…Consistent with this notion, we were able to detect NK-1 but not NK-2 or NK-3 mRNA in B cells (data not shown). Like in many other assays (21,23,25,26,42,43), HK-1 activity on B cells could be fully reproduced with SP, which is in accord with several earlier reports documenting enhanced Ig secretion in the presence of SP (44). Given the apparent functional overlap, an important issue is the tissue distribution of the two peptides.…”

Section: Discussionsupporting

confidence: 77%

“…As the first tachykinin peptide primarily expressed in non-neuronal tissues, the immunoregulatory function of HK-1 is of considerable interest. In T cells, HK-1 was found to enhance IFN-g production after Ag stimulation with equal potency to SP (42). More recently, Janelsins and colleagues demonstrated that both HK-1 and SP rescued bone marrow-derived dendritic cells (DCs) from apoptosis induced by the deprivation of growth factors, probably by activating the PI3K-Akt pathway.…”

Section: Discussionmentioning

confidence: 99%

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Hemokinin-1 Activates the MAPK Pathway and Enhances B Cell Proliferation and Antibody Production

Wang

Zhang

et al. 2010

The Journal of Immunology

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Hemokinin 1 (HK-1) is a substance P-like tachykinin peptide predominantly expressed in non-neuronal tissues. In addition to a prominent function in lymphoid development, recent studies indicate a potential role for HK-1 in immunoregulation. The current study was focused on its action on mature B cells. Despite the negligible effect on its own, HK-1 exhibited a profound influence on B cell activation elicited by several classical signals, including LPS stimulation, BCR cross-linking, and CD40 ligation. Cells therefore showed enhanced proliferation, survival, and CD80/86 expression, and produced more IgM with a higher frequency of Ab-forming cells. Biochemical analysis revealed that HK-1 alone was sufficient to induce the activation of MAPKs and the expression of Blimp-1 and Xbp-1 in B cells. Nevertheless, costimulation with a known B cell activator resulted in much enhanced phosphorylation of MAPKs and transcriptional activation of Blimp-1 and Xbp-1. Overall, these data support that HK-1 provides an important costimulatory signal for B cell activation, possibly through synergistic activation of the MAPK pathway and induction of transcription factors critical for plasmacytic differentiation.

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Section: Discussionsupporting

confidence: 77%

Section: Discussionmentioning

confidence: 99%

Hemokinin-1 Activates the MAPK Pathway and Enhances B Cell Proliferation and Antibody Production

Wang

Zhang

et al. 2010

The Journal of Immunology

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“…Another of the most regulated genes was tac4a, which encodes a family of species-divergent neurotransmitters called tachykinins (Page 2004(Page , 2006. Although the exact function of tac4 paralogs in zebrafish has not been unveiled, hemokinin 1 (Hk1), a product of the Tac4 gene, is reported to be expressed along with substance P at sites of chronic inflammation in mice (Metwali et al 2004), a typical NAFLD feature. It is well documented that the chronic inflammation caused by metabolic syndrome is one of the main causes of NAFLD evolution into NASH, which can eventually cause liver fibrosis, a process characterized by the deposition of new collagen and matrix molecules in the extracellular space.…”

Section: Model Characterizationmentioning

confidence: 99%

Liver immune responses to inflammatory stimuli in a diet-induced obesity model of zebrafish

Forn-Cuní¹,

Varela²,

Fernández-Rodrı́guez³

et al. 2014

Journal of Endocrinology

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Obesity-and metabolic syndrome-related diseases are becoming important medical challenges for the western world. Non-alcoholic fatty liver disease (NAFLD) is a manifestation of these altered conditions in the liver, and inflammation appears to be a factor that is tightly connected to its evolution. In this study, we used a diet-induced obesity approach in zebrafish (Danio rerio) based on overfeeding to analyze liver transcriptomic modulation in the disease and to determine how obesity affects the immune response against an acute inflammatory stimulus such as lipopolysaccharide (LPS). Overfed zebrafish developed an obese phenotype, showed signs of liver steatosis, and its modulation profile resembled that observed in humans, with overexpression of tac4, col4a3, col4a5, lysyl oxidases, and genes involved in retinoid metabolism. In response to LPS, healthy fish exhibited a typical host defense reaction comparable to that which occurs in mammals, whereas there was no significant gene modulation when comparing expression in the liver of LPS-stimulated and non-stimulated obese zebrafish at the same statistical level. The stimulation of obese fish represents a double-hit to the already damaged liver and can help understand the evolution of the disease. Finally, a comparison of the differential gene activation between stimulated healthy and obese zebrafish revealed the expected difference in the metabolic state between healthy and diseased liver. The differentially modulated genes are currently being studied as putative new pathological markers in NAFLD-stimulated liver in humans.

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“…Like SP, HK-1 can be expressed at sites of inflammation. It is produced by T cells and macrophages at least in the granulomas of murine schistosomiasis and in the gut (18). We showed that neither IL-12 nor IL-23 induces its expression in isolated splenic or LP T cells or macrophages cultured in vitro.…”

Section: Discussionmentioning

confidence: 84%

Interleukin-12 (IL-12) and IL-23 Induction of Substance P Synthesis in Murine T Cells and Macrophages Is Subject to IL-10 and Transforming Growth Factor β Regulation

et al. 2008

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Substance P is a tachykinin that enhances pathways of inflammation. Leukocytes at sites of intestinal inflammation make substance P. This study explored the role of interleukin-12 (IL-12), IL-23, and the regulatory cytokines IL-10 and transforming growth factor ␤ (TGF-␤) in controlling leukocyte substance P production. In murine schistosomiasis, it was found that IL-12 and IL-23 drive substance P gene expression and peptide synthesis in murine splenic T cells and macrophages, respectively. Cytokine induction of substance P synthesis both in T cells and in macrophages depends on intracellular NF-B activation and is Stat4 independent. IL-10 inhibits T-cell substance P production, while TGF-␤ blocks macrophage substance P expression. Intestinal macrophages also produce substance P, subject mostly to IL-23 and TGF-␤ regulation. Hemokinin is another tachykinin with homology to substance P. Macrophages and T cells make hemokinin, but hemokinin production is not subject to IL-12 or IL-23 regulation.Substance P (SP), an 11-amino-acid peptide, and its natural ligand the neurokinin 1 receptor (NK-1R) help regulate immune balance at mucosal surfaces and at other sites of chronic inflammation. SP derives from preprotachykinin A mRNA (PPT A), which is a product of the Tac 1 gene.SP is an important part of the Th1 pathways of inflammation, and its lack negatively affects the outcome of various infectious diseases. The granulomas of murine schistosomiasis display a completely functional SP immunoregulatory circuit (25). Experiments have shown that these granulomas are not normal if the mouse has a defect in the SP receptor (4). Thus, we study schistosomiasis to better understand how SP and its receptor function in inflammation. In the granulomas of murine schistosomiasis, SP made locally within the granulomas helps govern gamma interferon (IFN-␥) release (4). SP interacts with the SP receptor (NK-1R) expressed on the Th1 cells.The importance of SP in controlling the Th1 response also is evident in a murine model of salmonellosis, where treatment with an NK-1R antagonist diminishes the mucosal IFN-␥ response, leaving the animals more susceptible to the infection (13). SP also has a proinflammatory role in Th1 murine models of inflammatory bowel disease (9,23,27). Clostridium difficile can produce toxins in the intestines that induce colitis. NK1Rs, and by inference SP, help mediate C. difficile toxin-induced mucosal injury (6). Thus, the study of the SP immunoregulatory circuit in murine schistosomiasis has implications for other disease states too.Human, mouse, and rat leukocytes produce SP. It can come from T cells (14), macrophages (11,17,22), dendritic cells (15), or eosinophils (28). Lamina propria mononuclear cells (LPMC) isolated from the acutely injured murine intestines produce SP (5). Macrophages in the lamina propria of wild-type (WT) mice and interleukin-10 (IL-10)-deficient mice with colitis can make SP (1). T lymphocytes and macrophages make SP in both Th1-and Th2-type granulomas (1). Lipopolysaccharide may induce...

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Cutting Edge: Hemokinin Has Substance P-Like Function and Expression in Inflammation

Cited by 61 publications

References 30 publications

Hemokinin-1 Activates the MAPK Pathway and Enhances B Cell Proliferation and Antibody Production

Hemokinin-1 Activates the MAPK Pathway and Enhances B Cell Proliferation and Antibody Production

Liver immune responses to inflammatory stimuli in a diet-induced obesity model of zebrafish

Interleukin-12 (IL-12) and IL-23 Induction of Substance P Synthesis in Murine T Cells and Macrophages Is Subject to IL-10 and Transforming Growth Factor β Regulation

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