Increased circulating interleukin-12 (IL-12) p40 in pulmonary sarcoidosis

Abstract

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.

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

“…This lack of efficacy may possibly indicate that the IL-12 p40 mechanism is not a major determinant of the disease process, although it is unknown if higher doses would have impacted on the disease. The lack of efficacy of ustekinumab must be reconciled against the findings that active sarcoidosis skin lesions showed upregulation of IL-12 and IL-23 relative to control tissue [32] and increased IL-12 has been detected in sarcoidosis serum [26], bronchoalveolar lavage [25] and lymph nodes [45]. IL-12, in particular, has been thought to be a key driver of the dysregulation in interferon demonstrated in sarcoidosis [25,32,46].…”

“…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.…”

Multiplex immune serum biomarker profiling in sarcoidosis and systemic sclerosis

“…Analysis of median levels of individual cytokines confirmed previously published studies showing upregulation of IL-1b, IL-6, IL-8, IL-10, IL-12p40, IL-15, IL-17, TNF-RI, TNF-RII, MIP1a, MIP-1b, MCP-1, HGF and IP-10 in SSc patients [13][14][15][16][17][18][19][20][21][22][23] and upregulation of IL-8, TNF-RI, TNF-RII, IL-12p40, MIP-1a, MIP1b, MIG and IP-10 in sarcoidosis [24][25][26][27]. Novel findings, as far as we are aware, for other individual biomarkers included increased serum IFN-a, MIG, IP-10, DR5 and eotaxin levels in SSc patients and elevated serum levels of RANTES, DR5, EGF and HGF in sarcoidosis compared with healthy controls.…”

Cytokine modulators in the treatment of sarcoidosis

“…Other cytokines involved in pathogenesis of the disease include INFc, IL2, TGFb, IL8, IL18, IL12, IL10, IL23 and other molecules produced by alveolar macrophages and activated lymphocytes during inflammatory processes [12]. In particular, IL12, a Th1 cytokine mainly derived from antigen-presenting cells [13], induces the differentiation of naïve T cells into T helper 1 lymphocytes [14]. Several studies report an increase in IL-12 levels in tissue, BAL and serum of patients with sarcoidosis, demonstrating involvement of this cytokine in its pathogenesis [15].…”