Th1/Th2 Cytokine Expression and its Relationship with Tumor Growth in B Cell Non-Hodgkin's Lymphoma (NHL)

Abstract

AT helper 1 (Th1) immune response is considered more effective than T helper 2 (Th2) for anti-tumor immunity, but either response could potentially stimulate tumor cell growth in lymphomas. Moreover, both IL-4 and IL-2/IL-12 are used in experimental treatment models for non-Hodgkin's lymphoma (NHL) despite their differing ability to elicit Th2 or Th1 responses, respectively. Here, we investigate which T helper cytokines (Th1 or Th2) predominate in B cell NHL tissue and determine whether cytokine expression correlates with tumor cell growth, cell death, and survival in a series of 44 NHL patients. Overall, we observed both Th1 and Th2 cytokine expression at the mRNA level, detecting high levels of IFN-gamma, IL6 and IL-10 expression in the majority of tumors. Transcripts for the IL-12 subunits p35 (38 of 38) and p 40 (23 of 38) were frequently detected in NHL tissue, and high p40 levels were common in patients with a good prognosis. Furthermore, high IL-4 levels correlated with greater survival duration (P < 0.0024) but nor overall survival. Cytokine expression of IL-2, IFNgamma and IL-4 was significantly reduced in the high grade tumor group. Interestingly, there was a strong correlation between high IL-4 levels and reduced levels of apoptosis (P < 0.006) or proliferation (P < 0.0001), which has also been reported in leukemic models. This has important implications for the success of IL-4 as a treatment for low and high grade tumors.

IL-4 protects the B-cell lymphoma cell line CH31 from anti-IgM-induced growth arrest and apoptosis: contribution of the PI-3 kinase/AKT pathway

“…It acts to prevent apoptosis induced by a number of stimuli and thus could contribute to the abnormal outgrowth of cells in vivo. Indeed, high IL-4 levels have been associated with reduced apoptosis of non-Hodgkin's lymphoma [55]. Interestingly, primary mediastinal large B-cell lymphomas (PMBL) have been shown to contain constitutive activation of STAT6 without evidence of cytokine production [50].…”

“…On the other hand, classical Hodgkin's lymphoma Reed-Sternberg cells produce IL-13 and display IL-13-dependent STAT6 activation and enhanced survival [14]. These effects are thought to be regulated by the STAT6-mediated induction of Bcl-xL [14,50,55]. In contrast, IL-4 was able to substantially protect B cells isolated from STAT6-deficient animals from spontaneous apoptosis [13,15], indicating the contribution of another signaling pathway.…”

HGAL is a novel interleukin-4–inducible gene that strongly predicts survival in diffuse large B-cell lymphoma

“…29 Recently, an inverse association between tumor levels of IL-4 and lymphoma proliferation have been noted. 30 Consequently, it is possible that high mRNA expressions of HGAL and BCL6 are markers of tumors in which IL-4 exhibits antilymphoma effects. This group of DLBCL tumors has better clinical outcomes.…”

Role of tumor‐derived proinflammatory cytokines GM‐CSF, TNF‐α, and IL‐12 in the migration and differentiation of antigen‐presenting cells in cervical carcinoma

“…However, they did observe a trend that high production of the IL-12 protein was associated with an improved survival. Jones et al 40 examined IL-12p35 and IL-12p40 expression in B-cell non-Hodgkin lymphoma. In that study high IL-12p40 levels were common in patients with a favorable prognosis.…”