Date of Award
Doctor of Philosophy (Medical Science)
Dr. Stephen M. Collins
Inflammatory conditions of the gut, such as ulcerative colitis and Crohn's disease are associated with an alteration in intestinal motility. The mechanisms underlying altered motor function is unknown, but may be the result of alteration in smooth muscle and/or enteric nerve function. Recent studies using Trichinella spiralis (T.spiralis) infection of rats, as model of intestinal inflammation, have shown that the accompanying inflammatory response in these animals is associated with an altered enteric nerve function. These changes included a suppression of noradrenaline and acetylcholine release and an increased substance P content within the neuromuscular layer of the inflamed jejunum. Furthermore, there was an expression inflammatory cytokines within the mucosa and the deeper muscular layers of the jejunum within 12 hrs from the onset of T.spiralis infection. This elevation in cytokine expression occurred prior to the changes in myenteric neurotransmitters. It is therefore possible that inflammatory cytokines within neuromuscular layer cause a change in neurotransmitter release and content, and thus contribute to the altered gut motility observed in the nematode-infected rats.
Addition of exogenous IL-1β or TNFα to isolated longitudinal musclemyenteric plexus (LM-MP) preparations caused a suppression of stimulated noradrenaline release, which was tiem and concentration dependent. This suppressive action was biphasic in manner, displayign an early protein synthesis independent effect and a delayed protein synthesis dependent effect. Furthermore, the delayed suppressive action of these cytokines on noradrenaline release were dependent on prostanoid synthesis. On examination of a putative direct interaction between these cytokines and adrenergic nerves using a nerve varicosity preparations, only IL-1β was found to suppress the evoked noradrenaline release. This suppressive action by IL-1β was time- and concentration-dependent, and in part, mediated by prostanoids. Although incubation of TNFα alone with the varicosities was unable to induce a response, the presence of TNFα did potentiate IL-1β-induced suppression of noradrenaline release. The conclusions drawn from this study are that TNFα causes a suppression of noradrenaline release from myenteric nerves which is evident only in a multicellular preparation and ilkely involves intermediary cells and their products including prostaglandins and/or thromboxanes. This contrasts with IL-1β, which in addition to an indirect effect, also suppressed noradrenaline release by directly interacting with adrenergic nerve terminals.
IL-1β also caused an increase in substance P content within the myenteric plexus. The increase in this neuropeptide was time and concentration dependent, and could be depleted by scorpion venom. Immunohistochemical studies indicated that substance P was only found present within myenteric nerves. The IL-1β-induced increase in substance P was considered to be due to increased synthesis, since cycloheximide prevented the cytokine-stimulated increase substance P content induced by IL-1β. Moreover, the increase in substance P content was mediated by prostanoid synthesis, but not nerve growth factor. The conclusion drawn from these experiments is that IL-1β stimulates the synthesis of substance P within intrinsic nerves of the myenteric plexus.
A putative role of endogenous IL-1 in the alteration of neurotransmitters in the T.spiralis model of intestinal inflammation was examined using a selective IL-1 receptor antagonist (IL-1ra). Treatment of the animals with IL-1ra prior to T.spiralis infection attenuated the suppressed noradrenaline release and increased substance P content observed in the inflamed LM-MP preparations. Therefore the results fro these experiments and those preformed using exogenous IL-1β and TNFα support and notion that inflammatory cytokines alters myenteric neurotransmitters, resulting in a disruption of enteric nerve function and thereby contributing to alterations n intestinal motility.
Hurst, Suzanne Maria, "The immunomodulation of the enteric nervous system: The effect of cytokines on neurotransmitter release and content" (1994). Open Access Dissertations and Theses. Paper 2467.