Heat Shock protein-70 derived from tumor cells is highly immunogenic and induces specific anti-tumor immune response by directly activating cytotoxic CD8(+) T cells. Additionally, Hsp70 is known to be a strong activator of antigen presenting cells and therefore, up regulates the production of pro-inflammatory cytokines and chemokines. In this study, we have shown the effect of tumor-derived Hsp70 on the induction of delayed type hypersensitivity reaction in a T cell lymphoma bearing mice. The autologous Hsp70 augments contact hypersensitivity and delayed type hypersensitivity responses in mice challenged with allergen in vehicle and antigens respectively. The adoptive transfer of splenocytes derived from Hsp70 immunized mice is able to enhance delayed type hypersensitivity response in antigen challenged normal and DL-bearing host. Furthermore, adoptive transfer of macrophages incubated with autologous Hsp70 also enhances DTH reactivity in mice. The pro-inflammatory cytokines and C-C chemokines are found to be elevated in the DTH footpad extract of antigen challenged normal and DL-bearing mice. Increased production of IFN-gamma and MIP-1alpha+/- suggest that autologous Hsp70 augments the recruitment of antigen specific Th1 cells, which further secretes pro-inflammatory cytokines and C-C chemokines mediating the hypersensitivity reaction upon challenge with antigens.

R e t r a c t e d RetractionThe article from Clinical and Experimental Immunology, 'Interleukin-13-induced type II polarization of inflammatory macrophages is mediated through suppression of nuclear factor-kB and preservation of IkBa in a T cell lymphoma' , by P. Deepak, S. Kumar and A. Acharya (August 2007, 149(2) The retraction has been agreed due to lack of original data. R e t r a c t e dInterleukin-13-induced type II polarization of inflammatory macrophages is mediated through suppression of nuclear factor-kB and preservation of IkBa in a T cell lymphoma SummarySpontaneously arising transplantable T cell lymphoma, designated as Dalton's lymphoma (DL), is characterized by a highly invasive and deleterious nature almost completely paralysing the host immune system. The level of interleukin (IL)-13 is elevated in serum and ascitic fluid of the DL-bearing host. IL-13 is a potent immunosuppressive cytokine and is an alternative activator of macrophages that suppresses the production of nitric oxide (NO) and expression of inducible nitric oxide synthase (iNOS), and proinflammatory cytokines. The expression of iNOS and proinflammatory cytokines are dependent largely upon the activation of nuclear factor-kB (NF-kB). Activation of NF-kB involves the degradation of cytoplasmic inhibitor IkBa, allowing the nuclear translocation of NF-kB and thereby transcription of the iNOS gene. Therefore, in this study we sought to determine whether the alternative activation or type II polarization of macrophages induced by IL-13 is mediated by the suppression of NF-kB and cytoplasmic preservation of IkBa.Western blot analysis and electrophoretic mobility shift assay (EMSA) indicate that tumour-associated macrophages (TAM) or polarized type II macrophages are due to preserved protein expression of IkBa, and therefore suppressed NF-kB nuclear translocation. These findings suggest that IL-13 may operate through the suppression of NF-kB activation and preservation of IkBa.

IL-13 is a Th2 cytokine that suppresses the effector function and alters the phenotype and function of macrophages switching to alternatively activated or type II polarized macrophages. The type II polarized macrophages or M2 phenotype differ from normal macrophages greatly in terms of receptor expression, cytokine and NO production, that show tumor promoting function rather than tumoricidal function of classically activated macrophages. The chemokines CCL-22 and CCL-17 produced by either tumor cells or alternatively activated macrophages attract Th2 cells preferentially, which increase the local concentration of Th2 cytokines including IL-13 that further skewed the normal phenotype of macrophages at the site of the tumor micro-environment. Therefore, it is possible to restore the phenotype and function of alternatively activated macrophages by eliminating or blocking the activities of these cytokines. In the present investigation, we show that by blocking the activity/signaling of one of its major constituents IL-13, the iNOS expression and correspondingly NO production increases. The observation signifies its efficacy towards a novel approach for cancer therapy by modulating the function of tumor-associated macrophages (TAM) in vivo for the first time.

Chelerythrine is capable of inducing apoptosis DL cells in vitro and therefore, it could be useful in combating tumor growth and progression.

Heat shock protein 70 is highly conserved cytosolic protein which have important role in growth, development, and apoptosis. Hsp70 is well-known activator of macrophages and enhances the release of specific and non-specific effector molecules that have major role in tumor destruction and immunopotentiation of host. However, morphological effects of hsp 70 has not been carried out, therefore, morphological effects of hsp 70 on murine peritoneal macrophages were examined by light microscopy and scanning electron microscopy. Thioglycolate-induced peritoneal macrophages were prepared from BALB/c mice and cultured for 24 h in the presence of the hsp70. Tumor-associated macrophages treated with 10 μg/ml were varied in shape, mostly spindle shaped, i.e., stretched bidirectionally; surface ruffles were increased and their lamellipodia was prominent which suggest that hsp 70 treatment not only enhances the functional state of the peritoneal macrophages but also initiate immense morphological changes leading to increased endothelium adherence, increased antigen uptake, and increased migration to the inflammatory site.