IL-7 Up-Regulates TNF-α-Dependent Osteoclastogenesis in Patients Affected by Solid Tumor

Abstract

BackgroundInterleukin-7 (IL-7) is a potent regulator of lymphocyte development, which has also significant effects on bone; in fact it is a potent osteoclastogenic factor. Some human solid tumors produce high IL-7 levels, suggesting a potential IL-7 role on tumor development and progression.MethodologyWe studied 50 male patients affected by solid tumors, and their blood samples were collected at tumor diagnosis. PBMCs were isolated and cultured with/without IL-7 to study its influence on osteoclastogenesis. Serum and cell culture supernatant IL-7 levels were measured by ELISA. The quantitative analysis of IL-7 expression on T and B cells was performed by Real-Time PCR.Principal FindingsSerum IL-7 levels were highest in osteolytic cancer patients, followed by cancer patients without bone lesions, and then healthy controls. We showed the IL-7 production in PBMC cultures and particularly in monocyte and B cell co-cultures. A quantitative analysis of IL-7 expression in T and B cells confirmed that B cells had a high IL-7 expression. In all cell culture conditions, IL-7 significantly increased osteoclastogenesis and an anti-IL-7 antibody inhibited it. We demonstrated that IL-7 supports OC formation by inducing the TNF-α production and low RANKL levels, which synergize in promoting osteoclastogenesis.ConclusionsWe demonstrated the presence of high serum IL-7 levels in patients with bone metastasis, suggesting the use of serum IL-7 level as a clinical marker of disease progression and of bone involvement. Moreover, we showed the capability of IL-7 to stimulate spontaneous osteoclastogenesis of bone metastatic patients and to induce osteoclastogenesis in cancer patients without bone involvement. These findings add further details to the disclosure of the mechanisms controlling bone metastasis in solid tumors.

Bone metastases in gastric cancer follow a RANKL-independent mechanism

“…This result differs from our previously published data on osteotropic tumors, where we demonstrated that IL-7 was high in patients with spontaneous osteoclastogenesis, as it stimulated OC differentiation through RANKL (23). In the present study, in gastric cancer, we did not show the same mechanism since RANKL did not promote osteoclastogenesis.…”

“…In previous studies on bone metastases by solid tumors, we demonstrated a role of IL-7 in promoting osteoclastogenesis (23). Thus, we administered IL-7 serum levels in 31 gastric cancer patients.…”

Interactions between the immune system and bone

“…Primarily, researchers observed increased TNFα production by T cells both in ovariectomized mice [19] and postmenopausal women [2,20] . TNFα enhances OC formation by up-regulating stromal cell production of RANKL and M-CSF and by increasing the responsiveness of OC precursors to RANKL [5,21] . Besides, other studies showed a key role of T cell-produced TNFα in rheumatoid arthritis [3,22] , multiple myeloma [23,6] and bone metastasis [4,5] .…”

“…Inflammatory disease characterized by systemic and local bone loss is an interesting field with which to explore the relationship between activation of the immune system and bone remodelling. In the last few years, investigators have shed light on this topic and T cells have been recognized as key regulators of osteoclast (OC) and osteoblast (OB) [1] formation and activity in different pathological conditions, such as osteoporosis [2] , rheumatoid arthritis (RA) [3] , bone metastasis [4,5] and periodontitis [6,7] . Estrogen deprivation induces bone loss.…”

Expression analysis and functional activity of interleukin-7 splice variants

“…IL-7 plays an important role in immune reconstitution after bone marrow transplantation, 3 it contributes to immunopathology in arthritis 4 and IL-7-producing cancer cells mediate TNF-a-dependent osteoclastogenesis. 5 Overexpression of IL-7 leads to profound defects in B-and T-cell regulation including lymphoma formation 6,7 and IL-7-dependent homing of tumor cells to the skin. The plethora of work with IL-7 in physiology and immune pathology has been performed using the 'canonical' form of IL-7, which spans six exons present in 33 kb of the chromosomal band 8q12-13.…”