SUMMARYIn sarcoidosis, a T helper 1 (Th1) response is an essential event and the up-regulation of interleukin-12 (IL-12) has been detected in affected disease sites. In order to investigate the clinical usefulness of circulating IL-12, we measured the serum concentrations of IL-12 by ELISA and performed immunohistochemistry using specific MoAbs for IL-12 in the lungs and scalene lymph nodes of patients with sarcoidosis. The serum concentration of IL-12 p40 was detectable in all 45 patients with pulmonary sarcoidosis and 18 normal controls, whereas that of IL-12 p70 was undetectable. The serum concentrations of IL-12 p40 in pulmonary sarcoidosis were significantly higher than those of the normal controls, especially in cases with abnormal intrathoracic findings detected by chest roentogenogram. The serum concentrations of interferon-g (IFN-g ) also increased compared with those of normal controls and there was a significant positive correlation between the serum concentrations of IL-12 p40 and IFN-g . Furthermore, serum angiotensin-converting enzyme (ACE) and lysozyme, which are known to be useful markers for disease activity in sarcoidosis, correlated well with the serum concentrations of IL-12 p40. The positive 67 Ga scan group (for lung field) had significantly elevated serum IL-12 p40 levels compared with those of the negative group. No bioactivity of IL-12 p70 was detected in three sarcoid cases sera by using the IL-12 responsive cell line. Finally, the immunohistochemical approach revealed that IL-12 p40 was expressed in the epithelioid cells and macrophages of sarcoid lungs and lymph nodes. We concluded that the production of IL-12 p40 was far greater in the sera and we have demonstrated this to be a useful clinical marker for disease activity and the Th1 response in pulmonary sarcoidosis.

Lung cancer is one of the commonest causes of cancer death in developed countries. Recent evidence suggests that angoigenesis is related to poor prognosis in many solid tumors including non-small cell lung cancer (NSCLC). Angiogenesis is regulated by a complex interaction among growth factors and cytokines and influenced by proteolytic enzymes such as plasminogen activators and matrix metalloproteases, expression of adhesion molecules, and distribution of extracellular matrices. Fibroblasts, macrophages, mast cells, and endothelial cells themselves also affect angiogenesis. This review concentrates on angiogenic growth factors including vascular endothelial growth factor, angiopoietins, platelet derived endothelial growth factor, and basic fibroblast growth factor, proteases, adhesion molecules including vascular endothelial cadherin and integrins, osteopontin, and mast cell products in tumor angiogenesis of NSCLC.

Sarcoidosis is a systemic granulomatous disorder with a high rate of spontaneous regression. Clara cell 10‐kDa protein (CC10), the predominant product of nonciliated bronchiolar epithelial cells, is a potent immunoregulatory and anti‐inflammatory agent. CC10 levels were measured in sera and bronchoalveolar lavage (BAL) fluids from 31 sarcoidosis patients (nine progressive disease and 22 regressive disease) and their relevance to spontaneous regression investigated. The inhibitory effects of recombinant CC10 on interferon gamma (IFN‐γ) production were examined using lipopolysaccharide (LPS)‐stimulated sarcoid BAL fluid cells, and the blocking effects of monoclonal antibody TY‐5, directed against CC10, on CC10 function were also tested. Serum and BAL fluid CC10 levels in the regressive disease group were significantly higher than those in the progressive disease group (serum, p<0.05; BAL fluid, p<0.005) and healthy subjects (serum, p<0.0001; BAL fluid, p<0.005). CC10 inhibited, in part, IFN‐γ production from LPS‐stimulated sarcoid BAL fluid cells (CC10 inhibition: 1,000 ng·mL‐1, 30%; 100 ng·mL‐1, 14%). TY‐5 restored IFN‐γ production by blocking CC10 function. Sarcoidosis patients with regressive disease showed increased Clara cell 10‐kDa protein levels in their sera and bronchoalveolar lavage fluids. Clara cell 10‐kDa protein may be a regulator of the inflammatory process in sarcoidosis.

Clara cell 10-kD protein (CC10) exhibits potent antiinflammatory properties. G38A polymorphism was found in the CC10 gene. We investigated the genetic influence of the allele on the development of sarcoidosis using case control analysis in a Japanese population (265 sarcoidosis cases and 258 control subjects). The A allele frequency in sarcoidosis cases (45.1%) was significantly higher than healthy control subjects (34.9%, p = 0.0002). According to outcomes, we divided 223 patients with follow-up periods of 3 years or more into two subgroups (55 progressive and 168 regressive disease). The A allele frequency in patients with progressive disease was significantly higher than control subjects (odds ratio = 4.55; 95% confidence interval, 2.97-6.97; p < 0.0001), whereas that of regressive disease was not. The A/A genotypes had significantly lower bronchoalveolar lavage fluid CC10 levels than the G/G (nonsmokers, p = 0.0054, and smokers, p = 0.0045) and G/A genotypes (nonsmokers, p = 0.0022, and smokers, p = 0.0402). The reporter gene assay showed significantly lower reporter activities in the presence of interferon-gamma for the 38A construct than the 38G construct (p = 0.0177). The G38A polymorphism in the CC10 gene may influence protein expression and be associated with the development of progressive sarcoidosis.

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