Substance P promotes lymphocyte-endothelial cell adhesion preferentially via LFA-1/ICAM-1 interactions
Introduction
Tissue inflammation manifests as a result of infiltration of the site of insult/injury by polymorphonuclear cells, macrophages and lymphocytes. Recruitment of these cells is a multistep process initiated by their migration from the regional lymph nodes through the vasculature using multiple and intricate adhesion signals on endothelial cells and immune cells (Anderson and Shaw, 1993; Springer, 1994). Research data suggest that the expression and avidity of these adhesion molecules, on immune and endothelial cells, are regulated by a range of cytokines and chemoatractants (Thornhill et al., 1991; Furth et al., 1994), which play a pivotal role in the inflammatory process (Osborn, 1990; Butcher, 1991; Springer, 1990). Experimental evidence suggests that another class of regulatory peptides, neuropeptides, may play an equally important role in regulating the expression and avidity of the adhesion molecules on these cells (Matucci-Cerinic and Partsch, 1992; Marasco et al., 1981; Payan et al., 1986). Such a concept is based on the fact that lymphoid organs are extensively innervated and the innervating fibers modulate the function of lymph node cells by releasing neuropeptides (Felten et al., 1987; Lundberg et al., 1984).
Amongst the neuropeptides, Substance P (SP), an 11 amino acid residue peptide released by A delta and C afferent sensory nerve fibers in response to nociceptive stimuli, has been reported to be a potent chemotactic factor for human monocytes (Ruff et al., 1985) and a neutrophil activating factor (Serra et al., 1988), suggesting that SP may play an important role in acute and chronic, tissue inflammatory responses. This contention is also strengthened by a recent finding that human neutrophil adhesion to bronchial epithelial cells is increased by SP (DeRose et al., 1994).
In this study, therefore, we have investigated the effect of SP on the adhesion of lymphocytes to endothelial cells. Our data from in vitro adhesion assays suggest that SP upregulates the adhesion of splenocytes, EL4 T-cells and T lymphocytes to endothelial cells by acting both as an upregulator of ICAM-1 expression on endothelial cells, possibly as an LFA-1 activator on lymphocytes, and also as a chemoattractant for splenocytes and T lymphocytes. These data indicate that SP has potent proinflammatory properties and is an active participant of adhesion cascades during inflammation.
Section snippets
Antibodies and peptides
Anti-ICAM-1 antibody secreting clone YN1/1 (CRL1878) was purchased from ATCC and monoclonal antibodies to ICAM-1 Clone 3E2 (Pharmingen, Cat.No:01540D), VCAM-1 (Clone INCAM-110, Cat.No: 01810D), LFA-1 (Clone M17/4, Cat.No:01840D), VLA-4 (Clone R1-2, Cat.No:01270D), α5 integrin (Clone 5H1027, Cat No:01740D) and β7 integrin (Clone M293, Cat.No: 09321D) were purchased from Pharmingen, USA.
Substance P (Cat No: 7451) and SP antagonist [D-Arg1, D-Phe5, D-Trp7,9, Leu11] (Cat.No:7492) were purchased
Pretreatment of the endothelial cell lines with SP
Pretreatment of the endothelial cell lines with SP in concentrations ranging from 10−8 to 10−12 M enhanced lymphocyte, EL4 T cell and T cell adherence to these cells. As depicted in Fig. 1, the adhesion of EL4 T cells (a), T cells (b) and splenocytes (c) peaked at 10−10 M. Further decrease in SP concentration to 10−11 and 10−12 M reversed the adhesion of both T cells and splenocytes to control or below control levels. The data presented are representative of triplicate samples of a mean of
Discussion
The consensus model for the events involved in the adhesion and extravasation of leukocytes consists of the participation of three major types of adhesion molecules, namely, the selectins, the integrins and their counter receptors belonging to the Ig superfamily of molecules (Anderson and Shaw, 1993; Springer, 1994). The initial rolling of leukocytes on the venule, mediated by selectins, is followed by chemoattractant mediated triggering of integrin activation, which is a key step in the
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Effects of substance P on human cerebral microvascular endothelial cell line hCMEC/D3 are mediated exclusively through a truncated NK-1 receptor and depend on cell confluence
2022, NeuropeptidesCitation Excerpt :In the experimental autoimmune encephalomyelitis model, an NK-1R antagonist reduced the expression of disease markers such as ICAM-1 and vascular cell adhesion molecule-1 on the CNS endothelial cells (Nessler et al., 2006). Another animal study also showed that SP promotes lymphocyte-endothelial cell adhesion by preferentially upregulating lymphocyte function-associated antigen-1 (LFA-1) and ICAM-1 interaction (Vishwanath and Mukherjee, 1996). The aim of this study was to investigate the effect of SP on the characteristics of brain microvascular endothelial cells, the main cellular component of the BBB.
Autonomic nerve dysfunction and impaired diabetic wound healing: The role of neuropeptides
2020, Autonomic Neuroscience: Basic and ClinicalCitation Excerpt :It has been recently reported to promote the mobilization of endothelial progenitor cells in the wounded tissue of a murine model of type 2 diabetes and increase the amount of Yes-associated protein expression in the dermis (Um et al., 2017). Furthermore, it acts as a potent chemoattractant for immune cells, promotes elevated expression of endothelial leukocyte adhesion molecule-1 on human microvascular endothelial cells and leukocyte function-associated antigen-1 (LFA-1) on murine endothelial cells and lymphocytes and can raise the levels of an array of inflammation linked cytokines including TGF-beta, TNF-α, IL-1β, IL-2, IL-8, IL-6 from dendritic and T cells, neutrophils, macrophages and fibroblasts (Matis et al., 1990; Vishwanath and Mukherjee, 1996; Delgado et al., 2003; Ho et al., 1997; Lai et al., 1998; Lai et al., 2002; Lambrecht, 2001; Lambrecht et al., 1999; Weinstock et al., 1988; O'Connor et al., 2004; Schratzberger et al., 1997; Bulut et al., 2008; Felderbauer et al., 2007). Hence by generating a pro-inflammatory environment within the wound site SP plays a crucial role in the inflammatory and angiogenic phases of wound healing.
Topical application of substance P promotes wound healing in streptozotocin-induced diabetic rats
2015, CytokineCitation Excerpt :SP, a 10-amino acid neuropeptide, is released by the sensory nerve fibers during tissue insult and has been reported to be a mediator of inflammation in wound healing [6]. It binds to neurokinin-1 (NK-1) receptors and elicits vasodilatory action via nitric oxide, alters vascular permeability and enhances the delivery and accumulation of leukocytes to tissues for the expression of the local immune response [7], SP stimulates the production of various cytokines such as, tumor necrosis factor-alpha (TNF-α), interleukin-1beta (IL-1β), IL-2, IL-8 and IL-6, and growth factors namely, vascular endothelial growth factor (VEGF) and transforming growth factor-beta1 (TGF-β1), involved in wound healing [8–11]. It is also involved in the angiogenesis, epidermal cell proliferation, and capillary and fibroblast proliferation [12,13].
Involvement of the peripheral sensory and sympathetic nervous system in the vascular endothelial expression of ICAM-1 and the recruitment of opioid-containing immune cells to inhibit inflammatory pain
2010, Brain, Behavior, and ImmunityCitation Excerpt :In line with this finding, it was demonstrated that SP is capable of directly activating human umbilical and dermal microvascular endothelial cell to express increased levels of functional ICAM-1 (Nakagawa et al., 1993; Quinlan et al., 1998). In addition, previous data showed that SP promoted lymphocyte–endothelial cell adhesion preferentially via LFA-1/ICAM-1 interactions (Vishwanath and Mukherjee, 1996). Quinlan et al. (1999) even could identify specific elements in the regulatory domain of the ICAM-1 gene as necessary for SP-dependent transcriptional activation.
Localization and expression of substance P in transgenic mice overexpressing human APP751 with the London (V717I) and Swedish (K670M/N671L) mutations
2007, Brain ResearchCitation Excerpt :Neuroinflammation is considered to be one of the neuropathological hallmarks of AD, among amyloid plaques, intraneural tangles and synaptic failure (Eikelenboom et al., 2002; Selkoe, 2002). Substance P enhances the secretion of pro-inflammatory cytokines like IL-8 (Lieb et al., 1997) or IL-6 (by promoting the effect of Tumor necrosis factor-alpha (TNFα) or IL-1) (Palma et al., 1997) and TNF-α (Luber-Narod et al., 1994) in astrocytes additional to its chemotaxic potential (Vishwanath and Mukherjee, 1996). As well in endothelial cells, another part of the blood–brain barrier, substance P acts proinflammatory.