A Myeloid-Specific Lack of IL-4Rα Prevents the Development of Alternatively Activated Macrophages and Enhances Immunity to Experimental Cysticercosis.

To determine the role that the IL-4/IL13 receptor plays in the development of alternatively activated macrophages (AAM or M2) and their role in the regulation of immunity to the extraintestinal phase of the helminth parasite , we followed the infection in a mouse strain lacking the IL-4Rα gene (IL-4Rα) and in the macrophage/neutrophil-specific IL-4Rα-deficient mouse strain (LysMcreIL-4Rα or cre/LoxP). While 100% of -infected IL-4Rα (WT) mice harbored large parasite loads, more than 50% of th eIL-4Rα mice resolved the infection. Approximately 88% of the LysMcreIL-4Rα mice displayed a sterilizing immunity to the infection.

PKCδ regulates IL-12p40/p70 production by macrophages and dendritic cells, driving a type 1 healer phenotype in cutaneous leishmaniasis.

The protein kinase C (PKC) family is involved in the regulation of many intracellular signalling pathways. Here, we report that the PKCδ isoform regulates IL-12p40/p70 production in macrophages and DC and that PKCδ deficiency in mice transforms the 129/Sv healer to a non-healer strain during cutaneous leishmaniasis. Leishmania major-infected PKCδ(-/-) 129/Sv mice developed a rapid increase in footpad swelling and parasite burden with disease progression, leading to necrosis and ulceration similar to non-healer BALB/c mice.

Analyzing classical and alternative macrophage activation in macrophage/neutrophil-specific IL-4 receptor-alpha-deficient mice.

Macrophage activation can be divided into a classical and an alternative pathway. Interferon-gamma-induced, classically activated macrophages are indispensable for protective effector responses against intracellular pathogens. However, excessive inflammatory immune responses mediated by classical macrophage activation can also be detrimental to the host.

Interleukin-4-promoted T helper 2 responses enhance Nippostrongylus brasiliensis-induced pulmonary pathology.

The role of CD4(+) T-cell interleukin-4 (IL-4) receptor alpha (IL-4Ralpha) expression in T helper 2 (TH2) immune responses has not been defined. To examine this role, we infected CD4(+) T-cell IL-4Ralpha knockout (KO) mice with the parasitic nematode Nippostrongylus brasiliensis, which induces strong host TH2 responses. Although N.

Murine IL-4 is able to signal via chimeric human IL-4Ralpha/mouse gamma-chain receptor.

Human IL-4Ralpha binds to mouse gammac resulting in a chimeric receptor specific for human IL-4 but not mouse IL-4, providing in principle an inducible hIL-4 system. We investigated the in vitro and in vivo characteristics of human IL-4Ralpha transgenic mice on a mouse IL-4Ralpha-deficient background (hIL-4Ralpha Tg/mIL-4Ralpha(-/-)). The integrity of lymphocyte-specific hIL-4Ralpha expression in hIL-4Ralpha Tg/mIL-4Ralpha(-/-) mice was demonstrated by FACS analysis.

Protein kinase C delta is essential for optimal macrophage-mediated phagosomal containment of Listeria monocytogenes.

Activation of macrophages and subsequent "killing" effector functions against infectious pathogens are essential for the establishment of protective immunity. NF-IL6 is a transcription factor downstream of IFN-gamma and TNF in the macrophage activation pathway required for bacterial killing. Comparison of microarray expression profiles of Listeria monocytogenes (LM)-infected macrophages from WT and NF-IL6-deficient mice enabled us to identify candidate genes downstream of NF-IL6 involved in the unknown pathways of LM killing independent of reactive oxygen intermediates and reactive nitrogen intermediates.

Deletion of IL-4Ralpha on CD4 T cells renders BALB/c mice resistant to Leishmania major infection.

Effector responses induced by polarized CD4+ T helper 2 (Th2) cells drive nonhealing responses in BALB/c mice infected with Leishmania major. Th2 cytokines IL-4 and IL-13 are known susceptibility factors for L. major infection in BALB/c mice and induce their biological functions through a common receptor, the IL-4 receptor alpha chain (IL-4Ralpha).

Delayed goblet cell hyperplasia, acetylcholine receptor expression, and worm expulsion in SMC-specific IL-4Ralpha-deficient mice.

Interleukin 4 receptor alpha (IL-4Ralpha) is essential for effective clearance of gastrointestinal nematode infections. Smooth muscle cells are considered to play a role in the type 2 immune response-driven expulsion of gastrointestinal nematodes. Previous studies have shown in vitro that signal transducer and activator of transcription 6 signaling in response to parasitic nematode infection significantly increases smooth muscle cell contractility.

Impairment of alternative macrophage activation delays cutaneous leishmaniasis in nonhealing BALB/c mice.

Expressed on various cell types, the IL-4Ralpha is a component of both receptors for IL-4 and IL-13. Susceptibility of BALB/c mice to Leishmania major is believed to be dependent on the development of IL-4- and IL-13-producing Th2 cells, while IFN-gamma secretion by Th1 cells is related to resistance. Despite a sustained development of Th2 cells, IL-4Ralpha-deficient BALB/c mice are able to control acute cutaneous leishmaniasis, suggesting that IL-4Ralpha-bearing cells other than Th2 cells contribute to susceptibility.

IL-9 is a susceptibility factor in Leishmania major infection by promoting detrimental Th2/type 2 responses.

IL-9 is a cytokine produced by Th2 cells, induced during Leishmania major infection. Because the role of IL-9 in leishmaniasis is currently unknown, IL-9-deficient mice were generated by immunization with mouse IL-9 coupled to OVA. This produced strong and long-lasting neutralizing anti-IL-9 Abs in vivo.

Development of an anti-IL-12 p40 auto-vaccine: protection in experimental autoimmune encephalomyelitis at the expense of increased sensitivity to infection.

IL-12 and IL-23, which share the IL-12 p40 subunit, have been ascribed central roles in many autoimmune disorders. We describe here an anti-IL-12 (alphaIL-12) auto-vaccine that potentially blocks both factors in vivo. Immunization of mice with mouse IL-12 coupled to OVA or Pan DR epitope (PADRE) peptide induced Ab directed against the IL-12 p40 subunit, which prevented IFN-gamma production in response to IL-12 administration in vivo.

Alternative macrophage activation is essential for survival during schistosomiasis and downmodulates T helper 1 responses and immunopathology.

Macrophage/neutrophil-specific IL-4 receptor alpha-deficient mice (LysM(Cre)IL-4Ralpha(-/flox)) were generated to understand the role of IL-4/IL-13 responsive myeloid cells during Type 2 immune responses. LysM(Cre)IL-4Ralpha(-/flox) mice developed protective immunity against Nippostrongylus brasiliensis accompanied by T(H)2 development and goblet cell hyperplasia. In contrast, LysM(Cre)IL-4Ralpha(-/flox) mice were extremely susceptible to Schistosoma mansoni infection with 100% mortality during acute infection.