Enhanced expression of interleukin-1α and tumor necrosis factor receptor-associated protein 1 in ileal tissues of cattle infected with Mycobacterium avium subsp paratuberculosis

Infection with Mycobacterium avium subsp. paratuberculosis is associated with high levels of morbidity, decreased production, and early culling in dairy cattle. Clinical symptoms of Johne's disease include persistent diarrhea, inappetence, and resultant weight loss due to chronic inflammation of the small intestine. Although the presence or absence of intestinal lesions cannot be used as a definitive indicator of M. avium subsp. paratuberculosis infection, most infected cattle exhibit significant changes to intestinal mucosa, with the focus of pathology surrounding the ileal cecal junction. Typical pathology of M. avium subsp. paratuberculosis infection includes inflammation, thickening of the lumenal wall, and hyperplasia in draining lymph nodes. To further understand the pathology of Johne's disease, we compared the gene expression profiles of ileal tissues from Johne's disease-positive (n = 6), and Johne's disease-negative (n = 5) Holstein cattle. Gene expression profiles were compared with a bovine total leukocyte (BOTL-3) cDNA microarray. Genes that were expressed at significantly higher levels (> 1.5-fold; P < 0.05) in tissues from Johne's disease-infected animals relative to noninfected animals included those encoding tumor necrosis factor receptor-associated protein 1 (TRAF1), interieukin-1alpha (IL-1alpha), MCP-2, N-cadherin, and beta1 integrin (CD29). Dramatic upregulation of IL-1alpha (21.5-fold) and TRAF1 (27.5-fold) gene expression in tissues of Johne's disease-positive cows relative to tissues from control cows was confirmed by quantitative real-time PCR. Western blot analysis confirmed that IL-1alpha and TRAF1 mRNA levels resulted in increased protein expression in tissues of Johne's disease-positive cattle relative to tissues from control cattle. High levels of IL-1alpha can produce symptoms similar to those found in clinical Johne's disease. Taken together, the data presented in this report suggest that many outward symptoms of Johne's disease may be due to IL-1alpha toxicity. In addition, enhanced levels of TRAR1 could result in cells within the lesions of Johne's disease-positive cattle that are highly resistant to TNF-alpha-induced signaling.