Increased serum levels of interferon-gamma-inducible protein 10 and monokine induced by gamma interferon in patients with haemophagocytic lymphohistiocytosis

Abstract

We measured serum interferon-gamma-inducible protein 10 (IP-10) and monokine induced by gamma interferon (MIG) levels to investigate the role of these molecules in the pathophysiology of haemophagocytic lymphohistiocytosis (HLH). Serum IP-10 and MIG levels were significantly increased in patients with active HLH compared with those of healthy controls. Serum MIG levels decreased gradually during the course of disease in a patient who recovered without therapy. On the other hand, rapid reduction of MIG and IP-10 levels was observed after chemotherapy in a patient with severe HLH. IP-10 and MIG mRNA expression was enhanced in liver and spleen, and IP-10 mRNA expression was enhanced in bone marrow in the patients, suggesting activated macrophages that infiltrated in these organs as one of the main producers of these cytokines. Serum IP-10 and MIG levels showed a significant correlation with serum IFN-gamma levels. In addition, these chemokines had a significant correlation with fever and serum LDH levels, which are clinical indicators of disease activity of HLH. These results suggest that IP-10 and MIG which are produced by activated macrophages by the stimulation of IFN-gamma, play an important role in the pathophysiology of HLH, by recruitment of activated Th1 cells into the tissues or organs.

Fig. 1

Serum IP-10 and MIG levels in HLH. Serum IP-10 (a, b) and MIG (c, d) levels were determined in active phase of HLH, IM and healthy controls (a, c), and acute and remission phases of HLH (b, d). The differences of serum cytokine levels among 3 groups were analysed by Kruskal–Wallis test, and multiple comparison (Scheffe's test). The difference of the cytokine levels between active and remission phase of the disease was analysed by Wilcoxon test. *P < 0·05, **P < 0·01, NS not significant.

Fig. 2

Time course of serum IP-10 and MIG levels in patients with HLH. Serum IP-10 (•) and MIG (▴) levels were determined during the course of the disease in (a) patient 10 and (b) patient 5 (Table 1), together with IFN-γ (○) and IL-18 (□). VP-16, etoposide; PSL, prednisolone; CyA, cyclosporin A.

Fig. 3

IP-10 and MIG mRNA expression in various tissues. mRNA expression levels of IP-10 and MIG were determined by semiquantitative RT-PCR, as described in materials and methods. GAPDH mRNA expression was used as an internal control. PCR was performed on 10-folds serially diluted samples of cDNA for the comparison of IP-10 or MIG mRNA expression levels.