Increased Expression of IL-12 Receptor mRNA in Active Pulmonary Tuberculosis and Sarcoidosis

Abstract

Cytokines have been implicated in the pathophysiology and development of pulmonary diseases such as tuberculosis and sarcoidosis. In particular, the numbers of cells expressing Th1-type cytokines such as IFN-gamma and IL-12 are increased within the lungs of patients with these granulomatous diseases. As a factor promoting the commitment of naive lymphocytes to a Th1-type profile of cytokine expression, IL-12 may be pivotal in the cascade of proinflammatory events within the airways. In this study, we examined the expression of the IL-12 receptor (IL-12R) mRNA in bronchoalveolar lavage (BAL) fluid from patients with active pulmonary tuberculosis (n = 6) and active pulmonary sarcoidosis (n = 6), and from allergic asthmatics (n = 6) and normal control subjects (n = 6). Bronchoscopy with BAL was undertaken, and cell cytospins were examined using the technique of in situ hybridization. There was a significant increase in the numbers of cells expressing mRNA for both beta(1) and beta(2) subunits of the IL-12R in active pulmonary sarcoidosis (p < 0.02, p < 0.01, respectively) and active pulmonary tuberculosis (p < 0.01, p < 0.005, respectively) compared with normal control subjects. In contrast, the allergic asthmatic patients exhibited a significant decrease in the number of IL-12R mRNA-positive cells (both beta(1) and beta(2) subunits (p < 0.01, p < 0.005, respectively), compared with the normal control subjects. These patients did, however, exhibit a significant increase in IL-4R mRNA, which was not evident in those with either tuberculosis or sarcoidosis when compared with normal subjects (p < 0.05). Colocalization studies demonstrated that CD8+ve cells are a principal site for the expression of IL-12R in tuberculosis. In sarcoidosis, IL-12R was expressed both on CD4+ve and CD8+ve cells. The increased expression of receptors for IL-12 in granulomatous diseases such as pulmonary tuberculosis and sarcoidosis provides evidence supporting the commitment of lymphocytes to a Th1-type cytokine profile in vivo.

IL-12 and IL-18 Are Increased and Stimulate IFN-γ Production in Sarcoid Lungs

“…The interaction of CD40 and CD40 ligand may be a clue to the greater induction of IL-12 p70 in sarcoid BAL fluid cells than in normal BAL fluid cells. BAL fluid T cells in sarcoid cases showed enhanced expression of IL-12␤ 2 R (22) and most BAL fluid T cells differentiated into Th1 (or T cytotoxic 1) cells (24). The expression of IL-18R was also up-regulated in Th1 cells (35).…”

“…On the basis of recent Th1 and Th2 paradigms, the cytokine profile of sarcoidosis is Th1 dominant when disease activity is high (17)(18)(19). Recent studies have demonstrated enhanced expression of IL-12 (20 -22) and IL-12R (23,24) in sarcoid lungs. IL-18 expression was reported to be increased in the airway epithelial cells of sarcoid cases (25).…”

A Role for IL-12 Receptor Expression and Signal Transduction in Host Defense in Leprosy

“…Individuals with mutations in the IL-12R genes have increased susceptibility to infection by Mycobacteria and Salmonella (30,31). In studying patients with tuberculosis and sarcoidosis, lung T cells were found to express high levels of IL-12R␤2 in comparison to normal controlled subjects (32). Yet there is a recent report of an IL-12R␤1-independent pathway of IL-12 responsiveness in human T cells (33).…”

Safety and efficacy of ustekinumab or golimumab in patients with chronic sarcoidosis

“…In addition, alveolar macrophages from patients with sarcoidosis have been shown to produce interleukin (IL)-12 in addition to TNF-a, IL-1b, and IL-6 [20][21][22][23][24][25][26][27][28][29]. Overexpression of IL-12, by activated alveolar macrophages, results in enhanced Th-1 cell proliferation and activation, leading to the increased expression of the pro-inflammatory mediators IFN-c and TNF-a, and the secretion of cytokines and chemotactic factors that could, in turn, recruit and activate additional T-cells.…”