Upregulation of Th1 Cytokine Profile (IL-12, IL-18) in Bronchoalveolar Lavage Fluid in Patients with Pulmonary Sarcoidosis

Abstract

Sarcoidosis, a systemic granulomatous disease of unknown etiology, is characterized by a predominantly Th1 cytokine milieu, which is involved in its immunopathogenesis. The role of novel immunologic markers reflecting T cell activity of the sarcoid immunologic response needs to be determined. The present study aims to evaluate the role of the Th1 cytokine pattern by estimating the local and systemic levels of interleukin-12 (IL-12) and IL-18 in bronchoalveolar lavage fluid (BALF), induced sputum, and serum of patients with pulmonary sarcoidosis. We studied prospectively 20 patients (12 women, 8 men) of median age 46 years (range 25-65) with sarcoidosis and 10 normal subjects (5 women, 5 men) of median age 39 years (range 26-60). IL-12 and IL-18 levels were measured using ELISA kits. The IL-12 BALF levels were significantly higher in sarcoidosis patients than in healthy subjects (5.64 +/- 0.21 pg/mL vs. 5.16 +/- 0.15 pg/mL, p < 0.001). In addition, IL-18 levels were significantly increased in BALF samples (47.69 +/- 6.29 pg/mL vs. 16.73 +/- 3.00 pg/mL, p < 0.001). A statistically significant decrease in IL-12 serum levels was detected in the sarcoid population compared with controls (5.77 +/- 0.50 pg/mL vs. 7.87 +/- 2.00 pg/mL, p < 0.001). No significant differences were detected in IL-12 and IL-18 levels between patients and controls in induced sputum samples. Our data suggest a potential role of IL-12 and IL-18 in the local immunologic response in pulmonary sarcoidosis. Further large-scale studies are needed to define the precise role of IL-12 and IL-18 in the immunopathogenesis of this disorder.

Hypothesis: Sarcoidosis is a STAT1-mediated disease

“…T cells which best express γ-interferon are designated T H 1. This subset of T cells predominates in the broncho-alveolar lavage of patients with sarcoidosis [31; 32; 33]. Since γ-interferon induces STAT1 expression, a T H 1 mediated disease should be associated with increased expression of STAT1.…”

Dendritic Cells in the Pathogenesis of Sarcoidosis

“…Alternatively, sarcoidosis alveolar macrophages secrete anti-inflammatory diffusible factors, such as IL-10, prostaglandin E2 (PGE 2 ), and inducible nitric oxide synthase (iNOS) (45,60,61). These mediators inhibit DC maturation and production of IL-12, a Th1 T cell-polarizing cytokine involved in sarcoidosis immunopathogenesis (6,62). Therefore, although myeloid DCs accumulate in sarcoidosis lung, the DCs are phenotypically and functionally immature secondary to either intrinsic sarcoidosis DC characteristics or macrophage-mediated inhibition of maturation.…”

“…The mechanism by which IFN-a induces autoimmunity is still unclear, although IFN-a induces both MHC class II and co-stimulatory molecules on blood monocytes (118) and may enhance DC and macrophage antigen presentation to Th1 T cells (119). Th1 T cells are important mediators of sarcoidosis (62,120), lupus (121), and psoriasis immunopathogenesis (36,50). IFN-a also directly increases IFN-g and IL-2 production from T cells, thus promoting granuloma formation (122).…”

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.…”