Patients with Crohn’s disease or ulcerative colitis have reduced levels of an important regulator of the immune response—the receptor for granulocyte-macrophage colony-stimulating factor (GM-CSF)—according to a study by Jonathan Goldstein et al. in the July issue of Gastroenterology.
The inflammatory bowel diseases (IBD) ulcerative colitis and Crohn’s disease arise from dysregulated immune responses in the intestinal mucosa. Cells of the innate immune response (granulocytes, macrophages and dendritic cells) are believed to have defective functions result in reduced mucosal barrier function, delayed bacterial clearance, hyporesponsive neutrophils and defective secretion of cytokines. These defects can lead to chronic inflammation in the gastrointestinal tract.
The cytokine GM-CSF is an important regulator of the immune response—antibodies that neutralize it have been associated with ileitis in mice and with progressive ileal disease in patients with Crohn’s disease. The GM-CSF receptor (called CD116) is mostly expressed on myeloid lineages and on epithelial cells.
Goldstein et al. investigated whether immune cells from patients with IBD express different levels of CD116 than cells from healthy individuals; they measured levels of CD116 mRNA and surface protein on circulating leukocytes from 52 patients with IBD and 52 healthy controls.
The authors found that levels of CD116 protein were reduced on granulocytes and monocytes from patients with ulcerative colitis or Crohn’s disease, independently of disease severity and therapy. Although the authors do not know the mechanisms that reduce expression of CD116 on these cells, they stated that it was not likely to result from increased internalization or abnormal processing of CD116, because the levels of CD116 mRNA were also reduced in these cells.
Statistical analysis revealed that levels of CD116 could distinguish patients with IBD from healthy individuals with about 90% sensitivity and specificity. Goldstein et al. stated that these values compare well, and even exceed the positive predictive value of currently available diagnostic tests for IBD.
Binding of GM-CSF to its receptor activates several signaling pathways. One outcome of these pathways is phosphorylation and activation of the transcription factor STAT3, which regulates many genes that control immune responses. The decreased levels of CD116 on granulocytes corresponded with significant reductions in phosphorylation of STAT3 in granulocytes isolated from the patients (28% in patients, 73% in healthy people). STAT3-mediated signaling by granulocytes has been shown to direct neutrophil migration, promote bacterial killing and increase neutrophil proliferation and survival.
So loss of CD116 and STAT3 activity affects many aspects of the immune response in patients with IBD. However, it is unclear whether simply giving patients recombinant GM-CSF would be effective way to treat their IBD; the authors propose analyzing levels of the receptor CD116, to make sure patients can respond to the cytokine. In previous studies, CSFs were effective in only some patients with CD.
How might loss of GM-CSF signaling lead to IBD? Studies in mice have shown that GM-CSF contributes to immune tolerance. In an accompanying editorial, Glen Dranoff explains that the cytokine regulates intestinal homeostasis through several mechanisms (see figure). Paneth and hematopoietic cells can secrete GM-CSF, which regulates proliferation and survival of epithelial cells. GM-CSF is required for development of CD103+ dendritic cells, which support the generation of regulatory T cells. GM-CSF controls the activities of macrophages, which mediate the inflammatory response and mucosal repair. Neutrophils also require GM-CSF to function during infection and injury.
Dranoff states that the findings of Goldstein et al. strengthen the link between GM-CSF and IBD, but further investigations are required to determine whether reagents that alter GM-CSF signaling can be developed as therapeutics for IBD.
More Information on IBD:
Read the article online.
Goldstein JI, Kominsky DJ, Jacobson N. et al. Defective leukocyte GM-CSF receptor (CD116) expression and function in inflammatory bowel disease. Gastroenterology 2011;141:208–216.
Read the accompanying editorial.
Dranoff, G. Granulocyte-macrophage colony stimulating factor and inflammatory bowel disease: establishing a connection. Gastroenterology 2011;141:28–31.