Reciprocal Regulation of Substance P and IL-12/IL-23 and the Associated Cytokines, IFNγ/IL-17: A Perspective on the Relevance of This Interaction to Multiple Sclerosis

Abstract

The neuropeptide substance P (SP) exhibits cytokine-like properties and exerts different effects in autoimmune inflammation. Various immune cells express SP and its neurokinin-1 receptor (NK1R) isoforms. A role for SP has been demonstrated in a number of autoimmune conditions, including multiple sclerosis (MS). In this work, we studied the role of SP and NK1R in human immune cells with a focus on their relationship with IL-12/IL-23 family cytokines and the associated IFN-γ/IL-17. AIMS: (1) To determine the role of SP mediated effects on induction of various inflammatory cytokines in peripheral blood mononuclear cells (PBMC); (2) to investigate the expression of SP and its receptor in T cells and the effects of stimulation with IL-12 and IL-23. Quantitative real-time PCR, flow cytometry, ELISA, promoter studies on PBMC and primary T cells from healthy volunteers, and Jurkat cell line. Treatment with SP significantly increased the expression of IL-12/IL-23 subunit p40, IL-23 p19 and IL-12 p35 mRNA in human PBMC. Expression of NK1R and SP in T cells was upregulated by IL-23 but a trend was observed with IL-12. The IL-23 effect likely involves IL-17 production that additionally mediates IL-23 effects. Mutual interactions exist with SP enhancing the cytokines IL-23 and IL-12, and SP and NK1R expression being differentially but potentially synergistically regulated by these cytokines. These findings suggest a proinflammatory role for SP in autoimmune inflammation. We propose a model whereby immunocyte derived SP stimulates Th1 and Th17 autoreactive cells migrating to the central nervous system (CNS), enhances their crossing the blood brain barrier and perpetuates inflammation in the CNS by being released from damaged nerves and activating both resident glia and infiltrating immune cells. SP may be a therapeutic target in MS.Electronic supplementary materialThe online version of this article (doi:10.1007/s11481-015-9589-x) contains supplementary material, which is available to authorized users.

The lack of association between angiotensin‐converting enzyme gene insertion/deletion polymorphism and nicotine dependence in multiple sclerosis

“…Moreover, because of a high prevalence of major depressive disorder reported among MS patients (Siegert & Abernethy, 2005) and in line with the positive association between smoking behavior and the ACE‐I/D polymorphism among patients with depression (Baghai et al., 2008), it would be interesting to investigate the relevance of the ACE‐I/D polymorphism among those patients separately from other MS patients. Another issue that should be considered is that ACE, in addition to angiotensin II, has other potential substrates, some of which influence dopaminergic neurotransmission (and are proposed to be associated with MS), such as substance P and neurotensin (Binder, Kinkead, Owens, & Nemeroff, 2001; Krasnova, Bychkov, Lioudyno, Zubareva, & Dambinova, 2000; Soltys, Knight, Scharf, Pitt, & Mao‐Draayer, 2014; Vilisaar et al., 2015). …”

Substance P and Antagonists of the Neurokinin-1 Receptor in Neuroinflammation Associated with Infectious and Neurodegenerative Diseases of the Central Nervous System

“…Another study that used human peripheral blood mononuclear cells (PBMCs) evaluated the interactions of SP and NK1R with the IL-12/ IL-23 family of cytokines and the associated IFN-γ/IL-17 in the context of MS. Treatment of PBMCs with the specific NK1R antagonist CP-96,345 suppressed the up-regulation of IL-12 and IL-23 that was induced by SP stimulation 19 . Given the similarity of the in vitro results with those from the experiments in mice it is possible to suggest that NK1R antagonists are therapeutic candidates in MS.…”

“…These pathways are involved in neuroinflammation, neuronal excitation, cell survival and cell migration 14,17,18 . SP is capable of activating NFkB, which affects the regulation of various inflammatory genes, thus explaining its effects on chemotaxis and other inflammatory mechanisms 19 . The role of SP can be best described as that of a pleiotropic immune regulator.…”

“…Studies confirmed that SP-mediated signaling contributes to the maintenance of inflammation in the CNS during the chronic phase of EAE 35 and likely stimulates Th1 and Th17 autoreactive cells. These migrate to the CNS, enhance BBB crossing, and perpetuate inflammation 19 . Additionally, genome-wide linkage studies provided data to suggest that the SP precursor protein-encoding TAC1 gene is a possible susceptibility gene for MS 36,37 .…”

“…Activated T cells can then produce more SP, up-regulate NK1R, and stimulate antigen presenting cells to produce further T cell stimulatory cytokines. This positive feedback leads to an up-regulation of Th1 and Th17 responses, enhanced BBB permeability and perpetuation of inflammation 19 . Studies in the MS murine model EAE show evidence that SP-mediated signaling contributes to the maintenance of inflammation in the CNS during the chronic phase of the disease.…”