DOWN-REGULATION OF GAMMA-INTERFERON, TUMOR-NECROSIS-FACTOR TYPE-I, INTERLEUKIN-1 (IL-1) TYPE-1, IL-3, IL-4, AND TRANSFORMING GROWTH-FACTOR-BETA TYPE-I RECEPTORS AT THE LOCAL SITE DURING THE ACUTE-PHASE OF SHIGELLA INFECTION

An immunohistochemical technique was used to examine whether there was a colocalization of cytokine-specific receptors with cytokine-express ing cells. We have previously shown that there is extensive cytokine p roduction and secretion in the rectal mucosa in shigellosis (interleuk in 1 alpha [IL-1 alpha], IL-1 beta, IL-1ra, IL-4, IL-6, IL-8, IL-10, t umor necrosis factor alpha [TNP-alpha], TNF-beta, gamma interferon, gr anulocyte-macrophage colony-stimulating factor, and transforming growt h factor beta [TGF-beta]) (R. Raqib, A. A. Lindberg, B. Wretlind, P. K . Bardhan, U. Andersson, and J. Andersson, Infect. Immun. 63:289-296, 1995; R. Raqib, B. Wretlind, J. Andersson, and A. A. Lindberg, J. Infe ct. Dis. 171:376-384, 1995). Kinetics for receptor expression was comp ared with that for cytokine synthesis in the inflamed rectal mucosa fr om Shigella-infected patients during acute (2 to 6 days after onset of diarrhea) and convalescent (30 to 40 days after onset) stages. Quanti fication of receptor expression was assessed by computer-assisted anal ysis of video microscopic images. A selective down-regulation of the r eceptors for gamma interferon, tumor necrosis factor (TNF receptor [TN FR] type I), IL-1 (IL-1 receptor [IL-1R] types I and type II), IL-3, I L-4, and TGF-beta (TGF-beta receptor type I) was observed at the onset of the disease, with a gradual reappearance during the convalescent s tage. However, IL-2R, IL-6R, granulocyte-macrophage colony-stimulating factor receptor, TNFR type II, and TGF-beta receptor type II showed n o change in expression during the study period and were comparable to controls. Cytokine receptors were predominantly located to the epithel ial layer of the mucosal surface and crypts, with variable expression patterns in the lamina propria. A time-dependent kinetic curve was see n for the soluble IL-2R (sIL-2R), sIL-6R, and sTNFR types I and type I I shed in stool at the acute stage similar to that observed for cytoki ne secretion in stool but at four- to six-times-lower concentration. I n contrast, soluble receptor levels in plasma were 100-fold higher tha n the cytokine levels. The results suggest a dissociation in immune re gulation between cytokine production and cytokine receptor expression. The down-regulation of the receptors in acute shigellosis was probabl y a consequence of cytokine-induced internalization and shedding of th e receptors during signal transduction as well as due to programmed re gulatory roles played by cytokines and the bacterial antigens.