JOURNAL OF CELLULAR PHYSIOLOGY 201:167–180 (2004) REVIEW ARTICLE The Role of Substance P in Inflammatory Disease TERENCE M. O’CONNOR,1* JOSEPH O’CONNELL,1 DARREN I. O’BRIEN,1 TRIONA GOODE,1 1 1,2 CHARLES P. BREDIN, AND FERGUS SHANAHAN 1Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland 2Department of Medicine, Cork University Hospital, Cork, Ireland The diffuse neuroendocrine system consists of specialised endocrine cells and peptidergic nerves and is present in all organs of the body. Substance P (SP) is secreted by nerves and inflammatory cells such as macrophages, eosinophils, lymphocytes, and dendritic cells and acts by binding to the neurokinin-1 receptor (NK-1R). SP has proinflammatory effects in immune and epithelial cells and parti- cipates in inflammatory diseases of the respiratory, gastrointestinal, and muscu- loskeletal systems. Many substances induce neuropeptide release from sensory nerves in the lung, including allergen, histamine, prostaglandins, and leukotrienes. Patients with asthma are hyperresponsive to SP and NK-1R expression is increased in their bronchi. Neurogenic inflammation also participates in virus-associated respiratory infection, non-productive cough, allergic rhinitis, and sarcoidosis. SP regulates smooth muscle contractility, epithelial ion transport, vascular perme- ability, and immune function in the gastrointestinal tract. Elevated levels of SP and upregulated NK-1R expression have been reported in the rectum and colon of patients with inflammatory bowel disease (IBD), and correlate with disease activity. Increased levels of SP are found in the synovial fluid and serum of patients with rheumatoid arthritis (RA) and NK-1R mRNA is upregulated in RA synoviocytes. Glucocorticoids may attenuate neurogenic inflammation by decreasing NK-1R expression in epithelial and inflammatory cells and increasing production of neutral endopeptidase (NEP), an enzyme that degrades SP. Preventing the proinflammatory effects of SP using tachykinin receptor antagonists may have therapeutic potential in inflammatory diseases such as asthma, sarcoidosis, chronic bronchitis, IBD, and RA. In this paper, we review the role that SP plays in in- flammatory disease. J. Cell. Physiol. 201: 167–180, 2004. ß 2004 Wiley-Liss, Inc. The neuro-immune axis is a bidirectional pathway of The PPT-I gene can express four distinct forms of mRNA intersystem communication. Immune responses alter through alternative splicing, two of which (the b and g neural function, and in turn, neural activity modifies forms) encode synthesis of both SP and NKA, whilst the immunologic function. Inter-system cross-talk is medi- other two, the a and d forms, encode SP only (Nawa et al., ated via a common biochemical language of shared 1984). The b and g forms of PPT-I mRNA also encode the ligands such as cytokines and neuropeptides, and their synthesis of neuropeptide K and neuropeptide-g, which receptors. Mediators classically thought to be synthe- are amino-terminally extended forms of NKA, although sized exclusively by the nervous system, are now known their function has not been fully clarified (Tatemoto to be produced by immunocytes, and vice versa. The et al., 1985; Kage et al., 1988). The PPT-II gene gives rise diffuse neuroendocrine system consists of specialised to neurokinin B (Hokfelt et al., 2001). endocrine cells and peptidergic nerves and is present in all organs of the body, including the respiratory tract. Tachykinins are a family of neuropeptides that share the carboxy-terminal sequence Phe-X-Gly-Leu-Met- NH2, where X is an aromatic (Tyr or Phe) or hydrophobic (Val or Ile) amino acid (Uddman et al., 1997). This common sequence is essential for the tachykinin’s receptor interaction and activation, whereas the distinct amino-terminal sequences of the tachykinins provide Contract grant sponsor: Irish Lung Foundation. their receptor subtype specificity. Five tachykinin pep- *Correspondence to: Terence M. O’Connor, McMaster University, tides have been identified in mammals: substance P Health Sciences Center, Room 3U24, Cardiorespiratory Research (SP), neurokinin A, neuropeptide K, neuropeptide-g, Unit, 1200 Main Street West, Hamilton, Ontario L8N 3Z5, and neurokinin B. Canada or Department of Respiratory Medicine, Mercy Univer- In mammals, two separate genes encode the tachyki- sity Hospital, Cork, Ireland. E-mail: [email protected] nins designated preprotachykinin I (PPT-I) and pre- Received 22 September 2003; Accepted 9 January 2004DOI: protachykinin II (PPT-II) (Table 1) (Nawa et al., 1984). 10.1002/jcp.20061 ß 2004 WILEY-LISS, INC. 168 O’CONNOR ET AL. TABLE 1. Genes encoding synthesis of mammalian tachykinins noxious stimuli and modulates autonomic reflexes, including the micturition reflex. In the peripheral sys- Preprotachykinin Preprotachykinin I gene II gene tem, SP is localized in the primary sensory neurons and neurons intrinsic to the gastrointestinal, respiratory a-PPT-I mRNA PPT-II mRNA tracts, and genitourinary tracts (Maggi, 2000). Substance P (SP) Neurokinin B b-PPT-I mRNA SP, neurokinin A, neuropeptide K Tachykinin receptors g-PPT-I mRNA Tachykinin effects on target cells are mediated by at SP, neurokinin A, neuropeptide-g d-PPT-I mRNA least three specific receptors, the neurokinin-1 receptor SP (NK-1R), NK-2R, and NK-3R. These receptors are members of the superfamily of guanine nucleotide binding-coupled receptors, which interact with G- SUBSTANCE P proteins to promote high-affinity binding and signal SP was discovered by von Euler and Gaddum (1931). transduction (Hershey and Krause, 1990). These re- They reported that extracts of equine brain and ceptors are glycoproteins with seven putative a-helical intestine contained a hypotensive and spasmogenic transmembrane segments, an extracellular amino- factor. The preparation, termed preparation P, was terminus and an intracellular carboxyl tail (Fig. 1). G- later found to be proteinaceous. The isolation from protein-linked receptors are generally associated with bovine hypothalamus and characterization of SP was low abundance mRNA. For example, only 15 transcripts carried out by Leeman’s group in 1970–1971 (Chang per cell have been reported for the b2-adrenergic et al., 1971). The structure of SP is as follows. receptor (Hadcock et al., 1989). Each tachykinin appears to preferentially activate a SP : Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe distinct tachykinin receptor, although at high ligand -Gly-Leu-Met-NH2 concentration, each tachykinin can activate each of the tachykinin receptors. The NK-1R is activated SP is synthesized in the ribosome as a larger protein preferentially by SP, the NK-2R by NKA, and the NK- and then enzymatically converted into the active 3R by NKB (Nakanishi, 1991). The conserved carboxyl undecapeptide. The peptide is widely distributed in terminal domain of tachykinins interacts with the the central and peripheral nervous systems of verte- neurokinin receptors, while the unique amino terminal brates. In the central nervous system, SP is thought to sequences of tachykinins dictate receptor specificity. participate in various behavioral responses and in The relative affinity of NK-1R for neurokinin A and regulating neuronal survival and degeneration. SP also neurokinin B is 100- and 500-fold lower than for SP, regulates cardiovascular and respiratory function and is respectively (Gerard et al., 1991). Recently, a fourth involved in activating the emetic reflex. In the spinal tachykinin receptor has been cloned (Donaldson et al., cord, SP participates in neurotransmission of pain and 2001). Fig. 1. The neurokinin-1 receptor (NK-1R) is a glycoprotein with involved in agonist/antagonist binding, the third cytoplasmic loop is seven putative a-helical transmembrane segments, an extracellular responsible for G-protein interaction, while the cytoplasmic carboxyl amino-terminus and an intracellular carboxyl tail. The human NK-1R terminal contains many serine and threonine residues which when consists of 407 amino acid residues and has a relative molecular mass phosphorylated, cause desensitization of the receptor in response to of 46 kDa. The second and third membrane-spanning domains are repeated application of agonist. SUBSTANCE P IN INFLAMMATORY DISEASE 169 The human NK-1R consists of 407 amino acid residues lation of leukocytes to tissues for the expression of local and has a relative molecular mass of 46 kDa (Hopkins immune responses (Pernow, 1983). SP can specifically et al., 1991). The second and third membrane-spanning stimulate the chemotaxis of lymphocytes, monocytes, domains are involved in agonist/antagonist binding, neutrophils, and fibroblasts (Haines et al., 1993; Kahler the third cytoplasmic loop is responsible for G-protein et al., 1993; Schratzberger et al., 1997). SP has interaction, while the cytoplasmic carboxyl terminal been reported to induce the expression of endothelial- contains many serine and threonine residues which leukocyte adhesion molecule-1 on human microvascular when phosphorylated, cause desensitization of the re- endothelium, to increase the expression of the leukocyte ceptor in response to repeated application of agonist. integrin CD11b on human neutrophils, and to enhance Binding of SP to NK-1R mediates rapid endocytosis and the expression of intercellular adhesion molecular-1 internalization of the receptor; this also contributes to and leucocyte function-associated antigen-1 on murine desensitization of cells to SP signaling. Agonist stimula- endothelial cells, and lymphocytes (Matis et al., 1990; tion of the NK-1R in many