Obligatory Activation of SRC and JNK by GDNF for Survival and Axonal Outgrowth of Postnatal Intestinal Neurons.

The neurotrophin GDNF acts through its co-receptor RET to direct embryonic development of the intestinal nervous system. Since this continues in the post-natal intestine, co-cultures of rat enteric neurons and intestinal smooth muscle cells were used to examine how receptor activation mediates neuronal survival or axonal extension. GDNF-mediated activation of SRC was essential for neuronal survival and axon outgrowth and activated the major downstream signaling pathways.

MMP-9 Processing of Intestinal Smooth Muscle-derived GDNF is Required for Neurotrophic Action on Enteric Neurons.

The neurotrophin GDNF guides development of the enteric nervous system (ENS) in embryogenesis and directs survival and axon outgrowth in postnatal myenteric neurons in vitro. GDNF expression in intestinal smooth muscle cells is dynamic, with upregulation by inflammatory cytokines in vitro or intestinal inflammation in vivo, but the role of post-translational proteolytic cleavage is undefined. In a co-culture model of myenteric neurons, smooth muscle and glia, inhibition of serine or cysteine protease activity was ineffective against the >2-fold increase in axon density caused by TNFα.

M2 Macrophages and Phenotypic Modulation of Intestinal Smooth Muscle Cells Characterize Inflammatory Stricture Formation in Rats.

The progression of Crohn disease to intestinal stricture formation is poorly controlled, and the pathogenesis is unclear, although increased smooth muscle mass is present. A previously described rat model of trinitrobenzenesulfonic acid-induced colitis is re-examined here. Although inflammation of the mid-descending colon typically resolved, a subset showed characteristic stricturing by day 16, with an inflammatory infiltrate in the neuromuscular layers including eosinophils, CD3-positive T cells, and CD68-positive macrophages.

Epigenetic modification of intestinal smooth muscle cell phenotype during proliferation.

Inflammation causes proliferation of intestinal smooth muscle cells (ISMC), contributing to a thickened intestinal wall and to stricture formation in Crohn's disease. Proliferation of ISMC in vitro and in vivo caused decreased expression of marker proteins, but the underlying cause is unclear. Since epigenetic change is important in other systems, we used immunocytochemistry, immunoblotting, and quantitative PCR to examine epigenetic modification in cell lines from rat colon at low passage or after extended growth to evaluate phenotype.