Relevance of gamma interferon, tumor necrosis factor alpha, and interleukin-10 gene polymorphisms to susceptibility to Mediterranean spotted fever.

The acute phase of Mediterranean spotted fever (MSF) is characterized by dramatic changes in cytokine production patterns, clearly indicating their role in the immunomodulation of the response against the microorganism, and the differences in cytokine production seem to influence the extent and severity of the disease. In this study, the single nucleotide polymorphisms (SNPs) of tumor necrosis factor alpha (TNF-α) -308G/A (rs1800629) and interleukin-10 (IL-10) -1087G/A (rs1800896), -824C/T (rs1800871), and -597C/A (rs1800872) and the gamma interferon (IFN-γ) T/A SNP at position +874 (rs2430561) were typed in 80 Sicilian patients affected by MSF and in 288 control subjects matched for age, gender, and geographic origin. No significant differences in TNF-α -308G/A genotype frequencies were observed. The +874TT genotype, associated with an increased production of IFN-γ, was found to be significantly less frequent in MSF patients than in the control group (odds ratio [OR], 0.18; 95% confidence interval [95% CI], 0.06 to 0.51; P corrected for the number of genotypes [Pc], 0.0021). In addition, when evaluating the IFN-γ and IL-10 genotype interaction, a significant increase of +874AA/-597CA (OR, 5.31; 95% CI, 2.37 to 11.88; Pc, 0.0027) combined genotypes was observed. In conclusion, our data strongly suggest that finely genetically tuned cytokine production may play a crucial role in the regulation of the immune response against rickettsial infection, therefore influencing the disease outcomes, ranging from nonapparent or subclinical condition to overt or fatal disease

Characterization of two alternative Interleukin(IL)-10 5_UTR mRNA sequences, induced by lipopolysaccharide (LPS) stimulation of peripheral blood mononuclear cells

IL-10 production shows a broad-spectrum of individual response, suggesting a genetic component of approximately 75%. Different polymorphisms located close to, or within the IL-10 gene has been demonstrated to influence its transcription rate whereas the post-transcriptional regulation of IL-10 production has not well elucidated. The main responsible elements at this control level are both the 5\u2032- and 3\u2032-untranslated regions (UTR's) of mRNAs, and as the 3\u2032-UTR regions are mainly involved in the stability and decay rate of mRNAs, the 5\u2032-UTR regions mediate the binding rate of the molecule with ribosomal 40S subunit as a cis-acting element. Herein are report data on the identification of two IL10 mRNA that differ by the length of respective 5\u2032UTR regions (160 and 288 nucleotides, respectively; EMBL accession nrs: EU751618 and EU751619) produced after stimulation of human blood samples with bacterial lipopolysaccharide (LPS). The longer 5\u2032UTR is constitutively expressed in unstimulated PBMC cells cultured at 37 \ub0C for 24 h, while in LPS stimulated cells an additional IL-10 mRNA molecule, containing a shorter 5\u2032UTR, is synthesized. RNADRAW software (http://www.rnadraw.com/) analysis have indicated that the secondary structures of the shorter 5\u2032UTR IL-10 mRNA region is more available for the binding to the 40S ribosomal subunit. In conclusion, our data seem to suggest that LPS could influence the post-transcriptional control of IL-10 production inducing an alternative mRNA immediately available in response to the inflammatory stimulation