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Neuropeptide Substance P and the Immune Response

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Abstract and Figures

Substance P is a peptide mainly secreted by neurons and is involved in many biological processes, including nociception and inflammation. Animal models have provided insights into the biology of this peptide and offered compelling evidence for the importance of substance P in cell-to-cell communication by either paracrine or endocrine signaling. Substance P mediates interactions between neurons and immune cells, with nerve-derived substance P modulating immune cell proliferation rates and cytokine production. Intriguingly, some immune cells have also been found to secrete substance P, which hints at an integral role of substance P in the immune response. These communications play important functional roles in immunity including mobilization, proliferation and modulation of the activity of immune cells. This review summarizes current knowledge of substance P and its receptors, as well as its physiological and pathological roles. We focus on recent developments in the immunobiology of substance P and discuss the clinical implications of its ability to modulate the immune response.
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Neuropeptide substance P and the immune response
Alireza Mashaghi
Anna Marmalidou
Mohsen Tehrani
Peter M. Grace
Charalabos Pothoulakis
Reza Dana
Received: 28 January 2016 / Revised: 25 May 2016 / Accepted: 9 June 2016 / Published online: 17 June 2016
ÓSpringer International Publishing 2016
Abstract Substance P is a peptide mainly secreted by neu-
rons and is involved in many biological processes, including
nociception and inflammation. Animal models have pro-
vided insights into the biology of this peptide and offered
compelling evidence for the importance of substance P in
cell-to-cell communication by either paracrine or endocrine
signaling. Substance P mediates interactions between neu-
rons and immune cells, with nerve-derived substance P
modulating immune cell proliferation rates and cytokine
production. Intriguingly, some immune cells have also been
found to secrete substance P, which hints at an integral role of
substance P in the immune response. These communications
play important functional roles in immunity including
mobilization, proliferation and modulation of the activity of
immune cells. This review summarizes current knowledge of
substance P and its receptors, as well as its physiological and
pathological roles. We focus on recent developments in the
immunobiology of substance P and discuss the clinical
implications of its ability to modulate the immune response.
Keywords Immune regulation Neuropeptides
Cell-to-cell communication Signaling Cellular dynamics
Substance P (SP) is a highly conserved peptide that was
originally discovered in 1931 by Von Euler and Gaddum in
the equine brain and gut extracts—distinct from acetyl-
choline—capable of inducing hypotension and muscle
contraction [1]. This substance was purified and dried in
powder form (hence the name substance P) [2]; highly
conserved homologs were later identified in mice, rabbits,
and humans (Fig. 1a). SP is encoded by the TAC1 gene
(located on chromosome 7 in humans) and is a member of
the tachykinin peptide hormone family [3] (Fig. 1b); the
family also contains three other neuropeptides, also enco-
ded by TAC1, namely neurokinin A, neuropeptide K, and
neuropeptide c[4,5]. SP is expressed by many cell types
including neurons [69], astrocytes [10,11], microglia
[12], epithelial cells [13], and endothelial cells [14].
Immune cells, such as T cells [15], macrophages [16,17],
dendritic cells [18], or eosinophils [19] also display sig-
nificant levels of SP expression [16,15,20]. SP is also
expressed by some stem cells and progenitor cells [21],
including immunomodulatory mesenchymal stem cells
(MSC) [22]. Such widespread expression of SP in diverse
cell types may suggest its participation in a wide variety of
physiological and pathophysiological functions, by acti-
vating a multitude of signaling pathways.
The physicochemical properties of substance P underlie its
function. The SP peptide comprises 11 amino acids
(RPKPQQFFGLM-NH2) [23] with a net positive charge at
physiologic pH. Positively charged residues are located on
the N-terminus, while the C-terminus contains hydrophobic
A. Mashaghi and A. Marmalidou contributed equally to this work.
&Reza Dana
Schepens Eye Research Institute, Massachusetts Eye and Ear
Infirmary, Harvard Medical School, Boston, MA 02114, USA
Department of Psychology and Neuroscience, Center for
Neuroscience, University of Colorado, Boulder, CO 80309,
Division of Digestive Diseases, David Geffen School of
Medicine, Inflammatory Bowel Disease Center, University of
California, Los Angeles, Los Angeles, CA, USA
Cell. Mol. Life Sci. (2016) 73:4249–4264
DOI 10.1007/s00018-016-2293-z Cellular and Molecular Life Sciences
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
... However, little work has been done in the area of basic research work about the suitability of SP as a biomarker for pain in cattle so far. Studies in human medicine showed that SP plays a role in the activation of the immune system, chemotaxis of granulocytes, and migration of cells to the location of inflamed tissue [16,75]. SP concentrations increase during an inflammatory process [16,75,76]. ...
... Studies in human medicine showed that SP plays a role in the activation of the immune system, chemotaxis of granulocytes, and migration of cells to the location of inflamed tissue [16,75]. SP concentrations increase during an inflammatory process [16,75,76]. The same can be said for conditions of emotional stress [77]. ...
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Background Pain in cattle is a major welfare problem, as cattle mask their pain. Subjective and objective parameters to assess pain in cattle have been described. Among the objective parameters to evaluate pain in cattle is substance P (SP). SP is a neurotransmitter, which is involved in the processing of noxious information to the brain; it seems to be a more objective indicator for nociception than cortisol, which has long been used as a biomarker for pain and stress in cattle. The objective of this systematic review was to assess the existing literature about SP during painful procedures, conditions, and diseases in cattle in form of a systematic review. Results Following the PRISMA statement, 36 out of 236 studies were included in this systematic review. Study design, grouping, age and weight of animals, processing of blood samples for the assessment of SP, and results were heterogenous. The largest number of studies originated from the United States of America and Canada and were published in 2018. A higher number of studies were done on calves (69.4%, n = 25) compared with adult cattle (30.6%, n = 11). Most studies were done to assess SP concentrations after administration of analgesics prior to husbandry procedures in calves. Conclusions There is a manageable number of studies assessing SP concentrations during painful procedures, conditions, and diseases in cattle. SP seems to be a suitable biomarker for nociception in cattle, but results of research work are heterogenous, and SP concentrations of calves and adult cattle differ throughout studies. Basic research work is missing and is needed to assess factors others than nociception which might influence the SP concentrations in the blood plasma.
... SP is also expressed by epithelial cells, endothelial cells, and immunomodulatory mesenchymal stem cells [4,10,41]. Due to its ubiquitous expression by numerous cell types throughout the body, SP mediates diverse cell-specific physiological and pathological functions [42]. ...
... Elevated levels of SP in cornea and trigeminal ganglion have also been reported with DED symptoms in a menopause model using ovariectomized rats [141]. The high levels of SP trigger a neurogenic inflammatory response, which leads to the release of various pro-inflammatory cytokines in the ocular surface milieu [42]. The pro-inflammatory cytokines promote the maturation of antigen-presenting cells at the ocular surface, which migrate to dLNs and prime naïve T cells to generate CD4 + helper T cells, including Th17 cells [142,143]. ...
Substance P (SP) is a tachykinin expressed by various cells in the nervous and immune systems. SP is predominantly released by neurons and exerts its biological and immunological effects through the neurokinin receptors, primarily the neurokinin-1 receptor (NK1R). SP is essential for maintaining ocular surface homeostasis, and its reduced levels in disorders like diabetic neuropathy disrupt the corneal tissue. It also plays an essential role in promoting corneal wound healing by promoting the migration of keratocytes. In this review, we briefly discuss the structure, expression, and function of SP and its principal receptor NK1R. In addition, SP induces pro-inflammatory effects through autocrine or paracrine action on the immune cells in various ocular surface pathologies, including dry eye disease, herpes simplex virus keratitis, and Pseudomonas keratitis. We provide an in-depth review of the pathogenic role of SP in various ocular surface diseases and several new approaches developed to counter the immune-mediated effects of SP either through modulating its production or blocking its target receptor.
... SP has shown potent contraction of airway smooth muscle and promotion of plasma leakage properties owing to its biological and functional properties (40). It has been demonstrated that some immune cells have also been found to secrete SP, suggesting that it plays an indispensable role in immune response, such as chemotaxis of monocytes and eosinophils, degranulation of mast cells and eosinophils, enhancement of leukotrienes, and so on (41). Moreover, SP can also bind to its selective receptor neurokinin-1 receptor (NK-1R) via G-protein-coupled receptor pathway and exert a variety of biological effects (42). ...
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Asthma is a complex syndrome with polygenetic tendency and multiple phenotypes, which has variable expiratory airflow limitation and respiratory symptoms that vary over time and in intensity. In recent years, continuous industrial development has seriously impacted the climate and air quality at a global scale. It has been verified that climate change can induce asthma in predisposed individuals and that atmospheric pollution can exacerbate asthma severity. At present, a subset of patients is resistant to the drug therapy for asthma. Hence, it is urgent to find new ideas for asthma prevention and treatment. In this review, we discuss the prescription, composition, formulation, and mechanism of traditional Chinese medicine monomer, traditional Chinese medicine monomer complex, single herbs, and traditional Chinese patent medicine in the treatment of asthma. We also discuss the effects of Chinese herbal medicine on asthma from the perspective of cellular endocrinology in the past decade, emphasizing on the roles as intracellular and extracellular messengers of three substances—hormones, substances secreted by pulmonary neuroendocrine cells, and neuroendocrine-related signaling protein—which provide the theoretical basis for clinical application and new drug development.
... Calcitonin generelated peptide (CGRP), a pain-related neuropeptide, mainly released from sensory neurons (166), increases differentiation of Tregs in a model of EAE (167). On the other hand, substance P, a mediator for pain neurotransmission secreted at the end of sensory neuron nerve (168), was shown to impair Tregs function in murine dry eye disease model through the neurokinin 1 receptor, expressed on Tregs (169). Other signaling molecules, such as cytokines, produced by neuronal cells, may also regulate intestinal Tregs. ...
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The human gastrointestinal tract has an enormous and diverse microbial community, termed microbiota, that is necessary for the development of the immune system and tissue homeostasis. In contrast, microbial dysbiosis is associated with various inflammatory and autoimmune diseases as well as neurological disorders in humans by affecting not only the immune system in the gastrointestinal tract but also other distal organs. FOXP3+ regulatory T cells (Tregs) are a subset of CD4+ helper T cell lineages that function as a gatekeeper for immune activation and are essential for peripheral autoimmunity prevention. Tregs are crucial to the maintenance of immunological homeostasis and tolerance at barrier regions. Tregs reside in both lymphoid and non-lymphoid tissues, and tissue-resident Tregs have unique tissue-specific phenotype and distinct function. The gut microbiota has an impact on Tregs development, accumulation, and function in periphery. Tregs, in turn, modulate antigen-specific responses aimed towards gut microbes, which supports the host–microbiota symbiotic interaction in the gut. Recent studies have indicated that Tregs interact with a variety of resident cells in central nervous system (CNS) to limit the progression of neurological illnesses such as ischemic stroke, Alzheimer’s disease, and Parkinson’s disease. The gastrointestinal tract and CNS are functionally connected, and current findings provide insights that Tregs function along the gut-brain axis by interacting with immune, epithelial, and neuronal cells. The purpose of this study is to explain our current knowledge of the biological role of tissue-resident Tregs, as well as the interaction along the gut-brain axis.
The arterial vasculature can be divided into large conduit arteries, intermediate contractile arteries, resistance arteries, arterioles, and capillaries. Resistance arteries and arterioles primarily function to control systemic blood pressure. The resistance arteries are composed of a layer of endothelial cells oriented parallel to the direction of blood flow, which are separated by a matrix layer termed the internal elastic lamina from several layers of smooth muscle cells oriented perpendicular to the direction of blood flow. Cells within the vessel walls communicate in a homocellular and heterocellular fashion to govern luminal diameter, arterial resistance, and blood pressure. At rest, potassium currents govern the basal state of endothelial and smooth muscle cells. Multiple stimuli can elicit rises in intracellular calcium levels in either endothelial cells or smooth muscle cells, sourced from intracellular stores such as the endoplasmic reticulum or the extracellular space. In general, activation of endothelial cells results in the production of a vasodilatory signal, usually in the form of nitric oxide or endothelial-derived hyperpolarization. Conversely, activation of smooth muscle cells results in a vasoconstriction response through smooth muscle cell contraction. © 2022 American Physiological Society. Compr Physiol 12: 1-35, 2022.
Introduction: Ocular redness, or conjunctival hyperemia, is a common ophthalmic sign associated with reduced quality of life. For redness without apparent underlying pathology, topical ophthalmic decongestants have been widely used. Areas covered: Brimonidine tartrate was approved in 2017 as a topical vasoconstrictor at a 0.025% concentration for relief of ocular redness. Since then, investigators have reported on efficacy and safety findings from studies evaluating low-dose brimonidine for reducing ocular redness. Expert opinion: Brimonidine is highly selective for α2-adrenergic receptors. Clinical trials have so far shown that the drug in low doses significantly reduces ocular redness in comparison to vehicle for up to 8 hours. Brimonidine-treated eyes did not present side effects of other vasoconstrictors, such as hypotension, cardiac arrhythmia or drowsiness. Ocular adverse events such as allergic reactions and redness rebound were also minimal. In this review, we examine in detail published literature on the mechanism of brimonidine tartrate and its efficacy and safety in relieving conjunctival hyperemia.
Introduction Although acute mountain sickness (AMS) can be a life-threatening condition, early diagnosis is difficult due to vague and non-specific symptoms. The aim of this study is to investigate biochemical markers that can detect high-altitude diseases in advance. Eight different biomarkers (BNP, HIF-1α, NGAL, MMP-3, MMP-9, SESN2, substance P (SP), and U-II) were studied, and their relationship with AMS was investigated. Methods Of the 84 mountaineers who participated in the mountaineering training organized by the Turkish Mountaineering Federation in the Rize Kaçkar Mountains in 2018, 52 volunteered to participate in the study. Twelve hours after the participants reached an altitude of 2200 m (exposed to moderate hypoxia), their vital parameters were measured, and blood samples were taken for biochemistry tests. Vital signs and Lake Louise (LL) AMS scores were recorded every 24 h during the following 72 h. The participants were divided into two groups according to their LL scores: those with AMS and those without (AMS+ and AMS −), and the vital parameters and biomarker levels of both groups were compared and evaluated. Results Of the volunteers participating in the study, 35 (67.3%) were male and 17 (32.7%) were female, although there was no gender difference in terms of susceptibility to AMS. Among the investigated markers in the AMS + group, MMP-9 and SP were statistically significantly higher (p = 0.037 and p = 0.038, respectively). There were no statistical differences between AMS− and AMS+ groups with regard to heart rate, oxygen saturation, and systolic and diastolic blood pressure values (p = 0.507, p = 0.929, p = 0.955, p = 0.572, respectively). Conclusion There were significant differences between the AMS− and AMS+ groups in terms of MMP-9 and SP. However, differences in physical indexes between the groups were not statistically significant. This could provide objective indexes for scanning and screening individuals susceptible to AMS in the early stages of rapid ascending.
Objective: Incomplete spinal cord injury (SCI) is the most common spinal cord injury in clinic, however its mechanism is still not fully understood. Design: We constructed the rabbit spinal cord hemisection (SCH) model and used RT-PCR, western blotting, immunohistochemistry, and immunofluorescence experiments to explore the potential mechanism of SCI. Setting: The sham operation (SH) group, the observation (OB, which is the SCH) group, the OB+ substance p (SP) inhibitor group, the OB + NK1R inhibitor group, the OB + NK1R agonist group and the OB + SP inhibitor + NK1R agonist group. Participants: New Zealand white rabbits. Interventions: Use NK1R inhibitors, NK1R agonists, SP inhibitors to treat the SCH model. Outcome measures: IL-1β, IKKγ, IL-6 and NF-κB. Results: The results showed that nissl bodies, inflammatory cells and SP increased notably in the spinal cord cells of the rabbit SCH model. Through in vivo experiments with SP or NK1R inhibitors or NK1R agonists, we found that inhibiting SP/NK1R signaling can help improve SCH by inhibiting the release of pro-inflammatory cytokines IL-1β, IKKγ, IL-6 and NF-κB. Registered trials: Animal experiments were approved by Ruijin Hospital, Shanghai Jiaotong University School of Medicine.
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Immune cells and immune-derived molecules, endocrine glands and hormones, the nervous system and neuro molecules form the combined tridirectional neuroimmune network, which plays a significant role in the communication pathways and regulation at the level of the whole organism and local levels, in both healthy persons and patients with allergic rhinitis based on an allergic inflammatory process. This review focuses on a new research paradigm devoted to neuronal-immune cell units, which are involved in allergic inflammation in the nose and neuro-immune control of the nasal mucociliary immunologically active epithelial barrier. The categoriza-tion, cellular sources of neurotransmitters and neuropeptides, and their prevalent profiles in constituting allergen tolerance maintenance or its breakdown are discussed. Novel data on the functional structure of the nasal epithelium based on a transcriptomic technology, single-cell RNA-sequencing results, are considered in terms of neuroimmune regulation. Notably, the research of pathogenesis and therapy for atopic allergic diseases, including recently identified local forms, from the viewpoint of the tridirectional interaction of the neuroimmune network and discrete neuronal-immune cell units is at the cutting-edge.
Background: Ancient prescriptions of Suo Quan Wan (SQW) have therapeutic effects on diabetic bladder dysfunction. However, the underlying mechanism remains unclear. Here, we hypothesized that SQW ameliorates bladder overactivity and regulates neurotransmission via regulating Myosin Va protein expression. Methods: After diabetic rats were induced by streptozotocin (65 mg/kg), the model of diabetic bladder dysfunction was established by detecting fasting blood glucose, urodynamic test, in vitro muscle strip experiments, and histological examination. One week after induction, SQW was given to observe the therapeutic effect. The expression levels of Myosin Va in control, Model, SQW L and SQW H groups were detected by RT-qPCR, RNAscope and immunofluorescence assay. The expression levels of ChAT, SP, nNOS and VIP proteins were observed by immunofluorescence assay. After knockdown and overexpression of Myosin Va, the expression changes of ChAT, SP, nNOS and VIP and the regulatory role of SQW were observed. Results: STZ-induced DM rats had significantly higher serum glucose levels and lower body weight. Compared with the diabetic rats, SQW treatment significantly improved urination function with decreased residual volume (RV), bladder compliance (BC), non-voiding contractions (NVCs), and increased voided efficiency (VE). In addition, contractile responses of muscle strips to electrical-field stimulation (EFS), carbachol (CCh), KCl were significantly lower in the SQW H and SQW L groups than those in the model group. RT-qPCR found that the expression of Myosin Va in the bladder tissue or bladder neurons in model group was significantly increased compared with the control group, and SQW treatment significantly decreased the levels of Myosin Va. In DM rats, ChAT and SP expression were significantly increased, while nNOS and VIP expression were significantly decreased, and SQW improved this phenomenon. Interestingly, SQW ameliorated the abnormal expression of ChAT, SP, nNOS and VIP caused by myosin Va knockdown, and Myosin Va overexpression results are consistent with these. Conclusions: SQW ameliorates overactive bladder and regulate neurotransmission via regulating Myosin Va mRNA and protein expression.
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Corneal transplantation serves as a reproducible and simple surgical model to study mechanisms regulating immunity and angiogenesis. The simplicity of the model allows for systematic analysis of different mechanisms involved in immune and angiogenic privilege and their failures. This protocol describes how to induce neovessels and inflammation in an actively regulated avascular and immune-privileged site. This involves placing intra-stromal corneal sutures for two weeks, disrupting the privileges, and performing corneal transplantation subsequently. Privileged and non-privileged recipient responses to donor cornea can be compared to identify key immunological mechanisms that underlie angiogenesis and graft rejection. This protocol can also be adapted to the growing repertoire of genetic models available in the mouse, and is a valuable tool to elucidate molecular mechanisms mediating acceptance or failure of corneal graft. The model could be used to assess the potential of therapeutic molecules to enhance graft survival in vivo.
As a mediator of neurogenic inflammation and pain, we hypothesized that levels of the neuropeptide Substance P (SP) would be elevated in patients with sickle cell disease (SCD) with vaso-occlusive pain crisis. SP is a known stimulator of tumor necrosis factor- (TNF-) release and a promoter of interleukin-8 (IL-8), which are reported to be increased in SCD. These cytokines enhance adhesion of leukocytes to endothelium and may play a role in vaso-occlusive events. Serum levels of IL-8, TNF, and SP were studied in three groups of children aged 2 to 18 years: 30 well children with SCD, 21 with SCD in pain crisis, and 20 healthy age-matched controls. Serum levels of SP were elevated in all SCD patients and were highest in patients in pain crisis. The percentage of sera with detectable levels of IL-8 (>5.0 pmol/L) was increased in SCD patients as compared with the control group. IL-8 levels were similar for well SCD patients and those with pain. TNF levels were not significantly different among the three groups. In three children with SCD, SP was measured at baseline and again during pain crisis. In each case, serum levels during pain crisis were higher than they were when the patient was well. We conclude that levels of SP are high in patients with SCD and increase during pain crisis. These results imply that SP plays a prominent role in the pain and inflammation of SCD and may be a measurable laboratory marker of vaso-occlusive crisis. We speculate that neurokinin receptor antagonists may have a therapeutic potential in the treatment of crisis pain. © 1998 by The American Society of Hematology.
Tibia fracture in rodents induces substance P (SP)-dependent keratinocyte activation and inflammatory changes in the hindlimb, similar to those seen in complex regional pain syndrome (CRPS). In animal pain models spinal glial cell activation results in nociceptive sensitization. This study tested the hypothesis that limb fracture triggers afferent C-fiber SP release in the dorsal horn, resulting in chronic glia activation and central sensitization. At 4 weeks after tibia fracture and casting in rats, the cast was removed and hind paw allodynia, unweighting, warmth, and edema were measured, then the antinociceptive effects of microglia (minocycline) or astrocyte (LAA) inhibitors or an SP receptor antagonist (LY303870) were tested. Immunohistochemistry and PCR were used to evaluate microglia and astrocyte activation in the dorsal horn. Similar experiments were performed in intact rats after brief sciatic nerve electric stimulation at C-fiber intensity. Microglia and astrocytes were chronically activated at 4 weeks after fracture and contributed to the maintenance of hind paw allodynia and unweighting. Furthermore, LY303870 treatment initiated at 4 weeks after fracture partially reversed both spinal glial activation and nociceptive sensitization. Similarly, persistent spinal microglial activation and hind paw nociceptive sensitization were observed at 48 hours after sciatic nerve C-fiber stimulation and this effect was inhibited by treatment with minocycline, LAA, or LY303870. These data support the hypothesis that C-fiber afferent SP signaling chronically supports spinal neuroglia activation after limb fracture and that glial activation contributes to the maintenance of central nociceptive sensitization in CRPS. Treatments inhibiting glial activation and spinal inflammation may be therapeutic for CRPS.
Substance P (SP) regulates interferon-γ (IFN-γ) production through interaction with the SP receptor NK1 (SPr) on T cells at sites of inflammation. Using murine schistosomiasis, we evaluated whether SPr expression was subject to immunoregulation. Splenocytes from schistosome-infected mice cultured for ≤18 h did not express SPr, as determined by quantitative polymerase chain reaction assay. However, exposure to schistosome egg antigen (SEA) for ≤4 h induced strong receptor expression. Experiments using splenocytes fractionated with antibody-coupled, paramagnetic beads showed that induction localized exclusively to T cells. Receptor protein expression was confirmed with Western blot. Interleukin 12 (IL-12) also induced strong T-cell SPr expression. Both SEA and IL-12 remained strong inducers of T-cell SPr in lymphocytes from the IL-12 (p40) and IFN-γR double-knockout mouse, which suggested that SEA did not require IL-12 to induce SPr and that both worked independently of IFN-γ. Splenocytes from wild-type mice cultured with SEA and neutralizing anti-IL-12 monoclonal antibody (mAb) also showed SPr induction. However, anti-Ia mAb inhibited SEA induction of SPr. Thus, SPr is inducible on T cells. SEA induces SPr through interaction with T-cell receptor (TCR), independently of IL-12 and IFN-γ. IL-12 induces SPr independently of TCR activation and IFN-γ expression. SP and its receptor, which regulate IFN-γ production, are probably part of the IL-12-Th1 circuit.—Blum, A. M., Metwali, A., Crawford, C., Li, J., Qadir, K., Elliott, D. E., Weinstock, J. V. Interleukin 12 and antigen independently induce substance P receptor expression in T cells in murine schistosomiasis mansoni.